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	Ryan Nguyen, DO University of Illinois at Chicago Chicago, IL, USA LinkedIn		Elizabeth Buchbinder, MD Dana-Farber Cancer Institute Boston, MA, USA LinkedIn

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: some melanoma regimens can be found on dedicated pages:

39 regimens on this page 75 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

2022: Seth et al. Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update PubMed
- 2020: Seth et al. Systemic Therapy for Melanoma: ASCO Guideline PubMed

EDF/EADO/EORTC

2016: Garbe et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016 PubMed

ESMO

2020: Keilholz et al. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee PubMed
2020: Michielin et al. ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee PubMed

2019: Michielin et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2015: Dummer et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. PubMed
- 2012: Dummer et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Dummer et al. Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Dummer et al. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Dummer et al. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Jost. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Jost et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma PubMed
- 2003: Jost. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma PubMed

INMC

2019: Amaria et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium PubMed

NCCN

NCCN Guidelines - Melanoma: Cutaneous
- 2019: Coit et al. Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2016: Coit et al. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2014: Coit et al. Melanoma, Version 4.2014 PubMed
- 2013: Coit et al. Melanoma, version 2.2013: featured updates to the NCCN guidelines. PubMed
- 2012: Coit et al. Melanoma. PubMed
- 2012: Pfister et al. Mucosal melanoma of the head and neck. PubMed
- 2009: Coit et al. Melanoma. PubMed
- 2006: Houghton et al. Melanoma. PubMed
- 2004: Author not listed. Melanoma. Clinical practice guidelines in oncology. PubMed

SITC

2018: Sullivan et al. An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0 PubMed
- 2013: Kaufman et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma PubMed

Perioperative therapy

This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.

Pembrolizumab monotherapy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Patel et al 2023 (SWOG S1801)	2019-02 to 2022-05	Phase 3 (E-switch-ic)	Adjuvant Pembrolizumab	Superior EFS (primary endpoint) EFS24: 72% vs 49% (HR 0.59, 95% CI 0.40-0.86)

Eligibility criteria

Resectable stage IIIB to IV melanoma without brain metastasis

Neoadjuvant

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 3 cycles

Definitive

Local therapy

Complete resection

Adjuvant

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 15 cycles

References

SWOG S1801: Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. link to original article contains dosing details in manuscript PubMed NCT03698019

Neoadjuvant response criteria

2018: Tetzlaff et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma

Adjuvant therapy

Cisplatin & Temozolomide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lian et al. 2013	2007-2009	Randomized Phase 2 (E-esc)	1. Interferon alfa-2b	Superior RFS (co-primary endpoint)
Lian et al. 2013	2007-2009	Randomized Phase 2 (E-esc)	2. Observation	Superior OS (co-primary endpoint)

Preceding treatment

Surgery

Chemotherapy

Cisplatin (Platinol) 25 mg/m² IV once per day on days 1 to 3
Temozolomide (Temodar) 200 mg/m²/day PO on days 1 to 5

21-day cycle for 6 cycles

References

Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. link to original article contains dosing details in manuscript PubMed ChiCTR-TRC-11001798

Ipilimumab monotherapy

Example orders

Example orders for Ipilimumab (Yervoy) in melanoma

Regimen variant #1, 3 mg/kg x 1 year

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tarhini et al. 2019 (ECOG E1609)	2011-2014	Phase 3 (E-switch-ic)	1. Interferon alfa-2b	Seems to have superior OS (co-primary endpoint) OS60: 72% vs 67% (HR 0.78, 95.6% CI 0.61-0.99)
Tarhini et al. 2019 (ECOG E1609)	2011-2014	Phase 3 (E-switch-ic)	2. Ipilimumab; 10 mg/kg	Not reported

Eligibility criteria

Stage IIIB, IIIC, or IV melanoma

Preceding treatment

Complete resection

Immunotherapy

Ipilimumab (Yervoy) 3 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles

Regimen variant #2, 10 mg/kg x 1 year

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tarhini et al. 2019 (ECOG E1609)	2011-2014	Phase 3 (E-switch-ic)	1. Interferon alfa-2b	Did not meet co-primary endpoint of OS
Tarhini et al. 2019 (ECOG E1609)	2011-2014	Phase 3 (E-switch-ic)	2. Ipilimumab; 3 mg/kg	Not reported
Weber et al. 2017 (CheckMate 238)	2015-03-30 to 2015-11-30	Phase 3 (C)	Nivolumab	Inferior RFS

Note: 12-month recurrence-free survival (RFS) in this arm of CheckMate 238 was 61% overall; Stage IIIB or IIIC: 62% (95% CI: 56-66.5); Stage IV: 57.5% (95% CI: 46-67). In the experimental arm, it was 70.5% overall; Stage IIIB or IIIC: 72% (95% CI, 67-77); Stage IV: 63% (95% CI, 52-72.5).

Eligibility criteria

Stage IIIB, IIIC, or IV melanoma

Preceding treatment

Complete resection

Immunotherapy

Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles

Regimen variant #3, 3 years

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Eggermont et al. 2015 (EORTC 18071)	2008-2011	Phase 3 (E-RT-esc)	Placebo	Superior RFS¹ (primary endpoint) RFS60: 40.8% vs 30.3% (HR 0.76, 95% CI 0.64-0.89) Superior OS¹ (secondary endpoint) OS60: 65.4% vs 54.4% (HR 0.72, 95.1% CI 0.58-0.88)	Similar HRQoL²

¹Reported efficacy is based on the 2016 update.
²While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinical relevance.

Eligibility criteria

Stage III cutaneous melanoma

Preceding treatment

Complete resection

Immunotherapy

Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles, then 12-week cycle for 12 cycles (3 years)

References

EORTC 18071: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Karra Gurunath R, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Epub 2015 Mar 31. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. link to original article contains dosing details in manuscript PubMed NCT00636168
1. Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains dosing details in manuscript link to PMC article PubMed
2. HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to original article link to PMC article PubMed
3. Update: Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. link to original article PubMed
CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains dosing details in manuscript PubMed NCT02388906
1. Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01274338
1. HRQoL analysis: McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. Epub 2022 Aug 27. link to original article link to PMC article PubMed
SWOG S1404: Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. link to original article link to PMC article PubMed NCT02506153
1. HRQoL analysis: Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. link to original article link to PMC article PubMed

Ipilimumab & Nivolumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zimmer et al. 2020 (IMMUNED)	2015-2018	Randomized Phase 2 (E-esc)	1. Nivolumab	Not reported
Zimmer et al. 2020 (IMMUNED)	2015-2018	Randomized Phase 2 (E-esc)	2. Placebo	Superior RFS (primary endpoint) Median RFS: NYR vs 12.4 mo (HR 0.23, 97.5% CI 0.12-0.45) Seems to have superior OS¹ (secondary endpoint) Median OS: NYR vs NYR (HR 0.41, 95% CI 0.17-0.99)

¹Reported efficacy is based on the 2022 update.

Eligibility criteria

Stage IV melanoma

Preceding treatment

Resection or definitive radiotherapy, with NED

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1
Nivolumab (Opdivo) as follows:
- Cycles 1 to 4: 1 mg/kg IV once on day 1,
- Cycles 5 to 24: 3 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 14-day cycle for 20 cycles (1 year)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2022 (CheckMate 915)	2017-04 to 2018-06	Phase 3 (E-esc)	Nivolumab	Did not meet primary endpoint of RFS RFS24: 64.6% vs 63.2% (HR 0.92, 97.295% CI 0.77-1.09)

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority in this setting.

Eligibility criteria

Stage IIIB, IIIC, IIID, or IV melanoma

Preceding treatment

Complete resection

Immunotherapy

Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
Nivolumab (Opdivo) 240 mg IV once per day on days 1, 15, 29

42-day cycle for 9 cycles (1 year)

References

IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains dosing details in manuscript PubMed NCT02523313
1. Update: Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet. 2022 Oct 1;400(10358):1117-1129. Epub 2022 Sep 10. link to original article PubMed
CheckMate 915: Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03068455

Nivolumab monotherapy

Regimen variant #1, 240 mg flat dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2022 (CheckMate 915)	2017-04 to 2018-06	Phase 3 (C)	Ipilimumab & Nivolumab	Did not meet primary endpoint of RFS

Eligibility criteria

Stage IIIB, IIIC, IIID, or IV melanoma

Preceding treatment

Complete resection

Immunotherapy

Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycle for up to 26 cycles (1 year)

Regimen variant #2, 480 mg flat dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kirkwood et al. 2023 (CheckMate 76K)	2019-10-28 to 2021-11-03	Phase 3 (E-RT-esc)	Placebo	Superior RFS (primary endpoint) RFS12: 89 vs 79.4% (HR 0.42, 95% CI 0.30-0.59)

Eligibility criteria

Stage IIB or IIC melanoma

Preceding treatment

Complete resection

Immunotherapy

Nivolumab (Opdivo) 480 mg IV once on day 1

28-day cycle for 13 cycles (1 year)

Regimen variant #3, weight-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2017 (CheckMate 238)	2015-03-30 to 2015-11-30	Phase 3 (E-RT-switch-ic)	Ipilimumab	Superior RFS (primary endpoint) RFS12: 70.5% vs 60.8% (HR 0.65, 97.56% CI 0.51-0.83)
Zimmer et al. 2020 (IMMUNED)	2015-2018	Randomized Phase 2 (E-esc)	1. Ipilimumab & Nivolumab	Not reported
Zimmer et al. 2020 (IMMUNED)	2015-2018	Randomized Phase 2 (E-esc)	2. Placebo	Superior RFS (primary endpoint) Median RFS: 12.4 vs 6.4 mo (HR 0.56, 97.5% CI 0.33-0.94)

Eligibility criteria

CheckMate 238: Stage IIIB, IIIC, or IV melanoma
IMMUNED: Stage IV melanoma

Preceding treatment

CheckMate 238: Complete resection
IMMUNED: Resection or definitive radiotherapy, with NED

Immunotherapy

Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycle for up to 26 cycles (1 year)

References

CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains dosing details in manuscript PubMed NCT02388906
1. Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains dosing details in manuscript PubMed NCT02523313
CheckMate 915: Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03068455
CheckMate 76K: Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, Long GV. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023 Nov;29(11):2835-2843. Epub 2023 Oct 16. Erratum in: Nat Med. 2023 Nov 3. link to original article link to PMC article PubMed NCT04099251
PIVOT-12: NCT04410445

Pembrolizumab monotherapy

FDA-recommended dose

Regimen variant #1, adult dosing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Eggermont et al. 2018 (KEYNOTE-054)	2015-08 to 2016-11	Phase 3 (E-RT-esc)	Placebo	Superior RFS¹ (primary endpoint) RFS60: 55.4% vs 38.3% (HR 0.61, 95% CI 0.51-0.72)
Grossmann et al. 2022 (SWOG S1404)	2015-2017	Phase 3 (E-switch-ic)	1. HD-Interferon alfa-2b 2. Ipilimumab	Superior RFS (co-primary endpoint) (HR 0.77, 99.62% CI 0.59-0.99)
Luke et al. 2022 (KEYNOTE-716)	2018-2020	Phase 3 (E-RT-esc)	Placebo	Superior RFS² (primary endpoint) Median RFS: 37.2 mo vs NYR (HR 0.64, 95% CI 0.50-0.84)
Patel et al 2023 (SWOG S1801)	2019-02 to 2022-05	Phase 3 (C)	Perioperative Pembrolizumab	Inferior EFS
Weber et al. 2024 (KEYNOTE-942)	2019-07-18 to 2021-09-30	Phase 3 (C)	Pembrolizumab & mRNA-4157	Might have inferior RFS (primary endpoint) RFS18: 62% vs 79% (HR 1.78, 95% CI 0.98-3.24)

¹Reported efficacy for KEYNOTE-054 is based on the 2022 update.
²Reported efficacy for KEYNOTE-716 is based on the 2022 update.

Eligibility criteria

KEYNOTE-942: completely resected stage IIIB to IV

Preceding treatment

KEYNOTE-716: Complete regional lymphadenectomy, within 13 weeks
SWOG S1404: Complete resection, within 14 weeks

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #2, pediatric dosing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Luke et al. 2022 (KEYNOTE-716)	2018-2020	Phase 3 (E-RT-esc)	Placebo	Superior RFS² (primary endpoint) Median RFS: 37.2 mo vs NYR (HR 0.64, 95% CI 0.50-0.84)

¹Reported efficacy is based on the 2022 update.

Preceding treatment

KEYNOTE-716: Complete regional lymphadenectomy, within 13 weeks

Immunotherapy

Pembrolizumab (Keytruda) 2 mg/kg (maximum dose of 200 mg) IV once on day 1

21-day cycle for 18 cycles (1 year)

References

KEYNOTE-054: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains dosing details in manuscript PubMed NCT02362594
1. Update: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. Epub 2020 Sep 18. link to original article link to PMC article PubMed
2. Update: Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):643-654. Epub 2021 Apr 12. link to original article PubMed
3. HRQoL analysis: Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):655-664. Epub 2021 Apr 12. link to original article PubMed
4. Update: Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Boers-Sonderen M, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Lorigan P, Grebennik D, Krepler C, Marreaud S, Suciu S, Robert C. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evid. 2022 Nov;1(11):EVIDoa2200214. Epub 2022 Sep 10. link to original article PubMed
KEYNOTE-716: Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, de la Cruz Merino L, Khattak MA, Schadendorf D, Long GV, Ascierto PA, Mandala M, De Galitiis F, Haydon A, Dummer R, Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer RA, Kirkwood JM, Chen K, Diede SJ, Ahsan S, Ibrahim N, Eggermont AMM; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729. Epub 2022 Apr 1. link to original article PubMed NCT03553836
1. HRQoL analysis: Khattak MA, Luke JJ, Long GV, Ascierto PA, Rutkowski P, Schadendorf D, Robert C, Grob JJ, de la Cruz Merino L, Del Vecchio M, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Carlino MS, Mohr P, De Galitiis F, Ross MI, Eroglu Z, Chen K, Jiang R, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Kirkwood JM. Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study. Eur J Cancer. 2022 Nov;176:207-217. Epub 2022 Oct 3. link to original article PubMed
2. Update: Long GV, Luke JJ, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Mohr P, Dummer R, Gershenwald JE, Yoon CH, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Ascierto PA; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1378-1388. Epub 2022 Oct 18. link to original article PubMed
3. Update: Luke JJ, Ascierto PA, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Long GV. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol. 2024 May 10;42(14):1619-1624. Epub 2024 Mar 7. link to original article PubMed
SWOG S1404: Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02506153
1. HRQoL analysis: Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. link to original article link to PMC article PubMed
SWOG S1801: Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. link to original article contains dosing details in manuscript PubMed NCT03698019
KEYNOTE-942: Weber JS, Carlino MS, Khattak A, Meniawy T, Ansstas G, Taylor MH, Kim KB, McKean M, Long GV, Sullivan RJ, Faries M, Tran TT, Cowey CL, Pecora A, Shaheen M, Segar J, Medina T, Atkinson V, Gibney GT, Luke JJ, Thomas S, Buchbinder EI, Healy JA, Huang M, Morrissey M, Feldman I, Sehgal V, Robert-Tissot C, Hou P, Zhu L, Brown M, Aanur P, Meehan RS, Zaks T. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb 17;403(10427):632-644. Epub 2024 Jan 18. link to original article PubMed NCT03897881

Local therapy

Talimogene laherparepvec monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Andtbacka et al. 2015 (OPTiM)	2009-2011	Phase 3 (E-RT-switch-ooc)	GM-CSF	Superior DRR (primary endpoint) Seems to have superior OS¹ (secondary endpoint) (HR 0.79, 95% CI 0.62-1.00)

¹Reported efficacy is based on the 2019 update.
Note: Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.

Local therapy

Talimogene laherparepvec (Imlygic) as follows:
- Initially, to seroconvert HSV-seronegative patients: 1,000,000 pfu/mL SC intralesional injection once on day 1
- Thereafter: 100,000,000 pfu/mL SC intralesional injection once on day 1
- Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."

21-day course, then 14-day cycle for at least 12 cycles

Subsequent treatment

Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months

References

OPTiM: Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. Epub 2015 May 26. link to original article contains dosing details in manuscript PubMed NCT00769704
1. Update: Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. link to original article link to PMC article PubMed

Metastatic or unresectable disease, first-line

ABC

ABC: Abraxane (Paclitaxel nanoparticle albumin-bound), Bevacizumab, Carboplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kottschade et al. 2013 (N0775)	2008-2010	Randomized Phase 2 (E-esc)	Temozolomide & Bevacizumab	Seems to have superior PFS6 (primary endpoint)

Note: The doses listed here are the amended starting doses.

Chemotherapy

Paclitaxel, nanoparticle albumin-bound (Abraxane) 80 mg/m² IV once per day on days 1, 8, 15
Carboplatin (Paraplatin) AUC 5 IV once on day 1

Targeted therapy

Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

28-day cycles

References

N0775: Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00626405

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, 5/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yan et al. 2021 (BCH-MM-131101)	2014-2017	Randomized Phase 2 (C)	CP & Bevacizumab	Seems to have inferior OS

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV once on day 1
Paclitaxel (Taxol) 175 mg/m² IV once on day 1

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Flaherty et al. 2013 (ECOG E2603)	2005-2008	Phase 3 (C)	CP & Sorafenib	Did not meet primary endpoint of OS

Chemotherapy

Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
- Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, given second
Paclitaxel (Taxol) as follows:
- Cycles 1 to 4: 225 mg/m² IV over 3 hours once on day 1, given first
- Cycle 5 up to 10: 175 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 10 cycles

References

ECOG E2603: Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00110019
BCH-MM-131101: Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. link to original article contains dosing details in manuscript PubMed NCT02023710

Carboplatin & Paclitaxel (CP) & Bevacizumab

CPB: Carboplatin, Paclitaxel, Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yan et al. 2021 (BCH-MM-131101)	2014-2017	Randomized Phase 2 (E-esc)	CP	Seems to have superior OS (secondary endpoint) Median OS: 14 vs 9 mo (HR 0.61, 95% CI 0.41-0.92) Superior PFS (primary endpoint) Median PFS: 4.8 vs 3 mo (HR 0.46, 95% CI 0.31-0.695)

Chemotherapy

Carboplatin (Paraplatin) AUC 5 IV once on day 1
Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Targeted therapy

Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15

28-day cycles

References

BCH-MM-131101: Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. link to original article contains dosing details in manuscript PubMed NCT02023710

Carboplatin & nab-Paclitaxel

Regimen

Study	Dates of enrollment	Evidence
Kottschade et al. 2011 (N057E1)	2006-2007	Phase 2

Chemotherapy

Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, given second
Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

Supportive therapy

"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."

28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion

References

N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00404235

Cisplatin & Dacarbazine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ridolfi et al. 2002	1997-1999	Phase 3 (C)	Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Cisplatin (Platinol) 75 mg/m² IV once on day 1
Dacarbazine (DTIC) 800 mg/m² IV once on day 1

21-day cycle for 6 cycles

References

Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains dosing details in manuscript PubMed

Cisplatin, Dacarbazine, Paclitaxel

Regimen

Study	Dates of enrollment	Evidence
Papadopoulos et al. 2009	2000-04 to 2002-09	Phase 1/2

Note: This is the suggested phase 2 dosing.

Chemotherapy

Cisplatin (Platinol) 20 mg/m² IV over 60 minutes once per day on days 1 to 4
Dacarbazine (DTIC) 800 mg/m² IV once on day 1
Paclitaxel (Taxol) 120 mg/m² IV over 2 hours once per day on days 1 & 8

21-day cycles (see note)

References

Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. link to original article contains dosing details in manuscript PubMed

CVD (Vindesine)

CVD: Cisplatin, Vindesine, Dacarbazine

Regimen variant #1, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bajetta et al. 2006	1999-2003	Phase 3 (C)	Biochemotherapy	Did not meet primary endpoint of OS

Chemotherapy

Cisplatin (Platinol) 30 mg/m² IV once per day on days 1 to 3
Vindesine (Eldisine) 2.5 mg/m² IV once on day 1
Dacarbazine (DTIC) 250 mg/m² IV once per day on days 1 to 3

21-day cycles

Regimen variant #2, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jungnelius et al. 1998	NR	Phase 3 (E-esc)	Dacarbazine & Vindesine	Did not meet primary endpoint of OS

Chemotherapy

Cisplatin (Platinol) as follows:
- Cycles 1 to 3: 100 mg/m² IV over 30 minutes once on day 1
Vindesine (Eldisine) 3 mg/m² IV once per day on days 1, 8, 15, 22
Dacarbazine (DTIC) 250 mg/m² IV over 30 minutes once per day on days 1 to 5

28-day cycles

References

Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. link to original article contains dosing details in manuscript PubMed
Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. link to original article PubMed

Dacarbazine monotherapy

Example orders

Example orders for Dacarbazine (DTIC) in melanoma

Regimen variant #1, 850 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (CA184-024)	2006-2008	Phase 3 (C)	Dacarbazine & Ipilimumab	Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Dacarbazine (DTIC) 850 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen variant #2, 850 mg/m² q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schadendorf et al. 2006	2000-2003	Phase 3 (C)	Autologous peptide-pulsed monocyte-derived dendritic cells	Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Dacarbazine (DTIC) 850 mg/m² IV once on day 1

28-day cycles

Regimen variant #3, 900 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Daponte et al. 2013 (SICOG 0109)	2002-2007	Phase 3 (C)	1. Dacarbazine & Fotemustine 2. Dacarbazine & IFN alfa-2b 3. Dacarbazine, Fotemustine, IFN alfa-2b	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Dacarbazine (DTIC) 900 mg/m² IV once on day 1

21-day cycles

Regimen variant #4, 1000 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chapman et al. 1999	1991-1997	Phase 3 (C)	Dartmouth regimen	Might have inferior ORR
Bedikian et al. 2006 (AGENDA)	2000-2003	Phase 3 (C)	Dacarbazine & Oblimersen	Might have inferior OS Median OS: 7.8 vs 9 mo (HR 1.15, 95% CI 0.99-1.33)
Testori et al. 2008 (C-100-21)	2002-2004	Phase 3 (C)	Vitespen	Did not meet primary endpoint of OS
Bedikian et al. 2010	2002-2007	Phase 3 (C)	DHA-paclitaxel	Did not meet primary endpoint of OS
Ribas et al. 2013 (A3671009)	2006-03 to 2007-07	Phase 3 (C)	Tremelimumab	Did not meet primary endpoint of OS
Ugurel et al. 2017 (ChemoSensMM)	2008-2012	Phase 3 (C)	Chemosensitivity-directed therapy: 1. Cisplatin & Paclitaxel 2. Cytarabine & Treosulfan 3. Gemcitabine & Treosulfan	Did not meet primary endpoint of OS
Hersh et al. 2015 (CA033)	2009-04 to 2011-06	Phase 3 (C)	nab-Paclitaxel	Seems to have inferior PFS
Robert et al. 2014 (CheckMate 066)	2013-01 to 2014-02	Phase 3 (C)	Nivolumab	Inferior OS

Chemotherapy

Dacarbazine (DTIC) 1000 mg/m² IV once on day 1

21-day cycles

Regimen variant #5, 1000 mg/m², split doses, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Falkson et al. 2003 (ECOG E3690)	NR	Phase 3 (C)	1. DTIC & Interferon 2. DTIC & Tamoxifen 3. DTIC, Interferon, Tamoxifen	Seems to have inferior ORR

Chemotherapy

Dacarbazine (DTIC) 200 mg/m² IV once per day on days 1 to 5

28-day cycles

Regimen variant #6, 1250 mg/m², split doses, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Middleton et al. 2000b	1995-1997	Phase 3 (C)	Temozolomide	Did not meet primary endpoint of OS

Chemotherapy

Dacarbazine (DTIC) 250 mg/m² IV over 20 to 30 minutes once per day on days 1 to 5

21-day cycles

Regimen variant #7, 1250 mg/m², split doses, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Avril et al. 2004	1998-2000	Phase 3 (C)	Fotemustine	Seems to have inferior ORR

Chemotherapy

Dacarbazine (DTIC) 250 mg/m² IV over 20 to 30 minutes once per day on days 1 to 5

28-day cycles

References

ECOG E3690: Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; ECOG. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. link to original article contains dosing details in manuscript PubMed
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. link to original article contains dosing details in manuscript PubMed
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains dosing details in manuscript PubMed
Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains dosing details in manuscript PubMed
Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. link to original article contains dosing details in abstract PubMed
AGENDA: Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. Epub 2006 Sep 11. link to original article contains dosing details in manuscript PubMed NCT00518895
C-100-21: Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. link to original article does not contain dosing details PubMed
Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. link to original article link to PMC article contains dosing details in manuscript PubMed
CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains dosing details in manuscript PubMed NCT00324155
1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article link to PMC article PubMed
A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00257205
SICOG 0109: Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01359956
CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains dosing details in manuscript PubMed NCT01721772
1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
2. Update: Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. link to original article link to PMC article PubMed
CA033: Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00864253
ChemoSensMM: Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00779714

Dacarbazine & Ipilimumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (CA184-024)	2006-2008	Phase 3 (E-esc)	Dacarbazine	Superior OS¹ (primary endpoint) Median OS: 11.2 vs 9.1 mo (HR 0.69, 95% CI 0.57-0.84)

¹Reported efficacy is based on the 2015 update.

Chemotherapy

Dacarbazine (DTIC) as follows:
- Cycles 1 to 8: 850 mg/m² IV once on day 1

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 10 mg/kg IV once on day 1
- Cycle 9 onwards: 10 mg/kg IV once on day 1

21-day cycle for 8 cycles, then 12-week cycles

References

CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains dosing details in manuscript PubMed NCT00324155
1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article link to PMC article PubMed

Dacarbazine & Vindesine

DV: Dacarbazine & Vindesine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jungnelius et al. 1998	NR	Phase 3 (C)	CVD	Did not meet primary endpoint of OS

Chemotherapy

Dacarbazine (DTIC) 250 mg/m² IV over 30 minutes once per day on days 1 to 5
Vindesine (Eldisine) 3 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. link to original article contains dosing details in manuscript PubMed

Fotemustine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Avril et al. 2004	1998-2000	Phase 3 (E-switch-ic)	Dacarbazine	Seems to have superior ORR (primary endpoint)

Chemotherapy

Fotemustine (Muphoran) as follows:
- Cycle 1: 100 mg/m² IV once per day on days 1, 8, 15
- Cycle 2 onwards: 100 mg/m² IV once on day 1

8-week course, then 21-day cycles

References

Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains dosing details in manuscript PubMed

Ipilimumab monotherapy

Example orders

Example orders for Ipilimumab (Yervoy) in melanoma

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Larkin et al. 2015 (CheckMate 067)	2013-07 to 2014-03	Phase 3 (C)	1. Ipilimumab & Nivolumab	Inferior OS¹	Equivalent HRQoL
Larkin et al. 2015 (CheckMate 067)	2013-07 to 2014-03	Phase 3 (C)	2. Nivolumab	Inferior OS¹	Equivalent HRQoL
Postow et al. 2015 (CheckMate 069)	2013-09-16 to 2014-02-06	Phase 3 (C)	Ipilimumab & Nivolumab	Inferior PFS

¹Reported efficacy for CheckMate 067 is based on the 2021 update.

Immunotherapy

Ipilimumab (Yervoy) 3 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles

References

CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01927419
1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. link to original article link to PMC article PubMed
CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01844505
1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article link to PMC article PubMed
2. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. link to original article link to PMC article PubMed
3. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
4. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
5. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. link to original article link to PMC article PubMed

Ipilimumab & Nivolumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Larkin et al. 2015 (CheckMate 067)	2013-07 to 2014-03	Phase 3 (E-RT-esc)	1. Ipilimumab	Superior OS¹ (co-primary endpoint) Median OS: 72.1 vs 19.9 mo (HR 0.42, 95% CI 0.35-0.51)	Equivalent HRQoL
Larkin et al. 2015 (CheckMate 067)	2013-07 to 2014-03	Phase 3 (E-RT-esc)	2. Nivolumab	Seems to have superior PFS¹ (co-primary endpoint) Median PFS: 11.5 vs 6.9 mo (HR 0.79, 95% CI 0.65-0.97)	Equivalent HRQoL

¹Reported efficacy is based on the 2021 update.
Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1
Nivolumab (Opdivo) as follows:
- Cycles 1 to 4: 1 mg/kg IV once on day 1
- Cycle 5 onwards: 3 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 14-day cycles

Regimen variant #2, "NIVO1+IPI3", weight-based maintenance

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Postow et al. 2015 (CheckMate 069)	2013-09-16 to 2014-02-06	Phase 3 (E-esc)	Ipilimumab	Superior PFS (secondary endpoint) Median PFS: NYR vs 4.4 mo (HR 0.40, 95% CI 0.23-0.68) Superior ORR (primary endpoint)

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1, given second
Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first

21-day cycle for 4 cycles, then 14-day cycles

Regimen variant #3, "NIVO1+IPI3", flat-dose maintenance

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Lebbé et al. 2019 (CheckMate 511)	2016-04-04 to 2017-03-27	Phase 3b/4 (C)	Ipilimumab & Nivolumab; NIVO3+IPI1	Not evaluated	More grade 3 to 5 TRAEs

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1
Nivolumab (Opdivo) as follows:
- Cycles 1 to 4: 1 mg/kg IV once on day 1
- Cycle 5 onwards: 480 mg IV once on day 1

21-day cycle for 4 cycles, then 28-day cycles

Regimen variant #4, "NIVO3+IPI1", flat-dose maintenance

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Lebbé et al. 2019 (CheckMate 511)	2016-04-04 to 2017-03-27	Phase 3b/4 (E-switch-ic)	Ipilimumab & Nivolumab; NIVO1+IPI3	Not evaluated	Fewer grade 3 to 5 TRAEs

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 1 mg/kg IV once on day 1
Nivolumab (Opdivo) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1
- Cycle 5 onwards: 480 mg IV once on day 1

21-day cycle for 4 cycles, then 28-day cycles

References

CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01927419
1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. link to original article link to PMC article PubMed
CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01844505
1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article link to PMC article PubMed
2. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. link to original article link to PMC article PubMed
3. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
4. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
5. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24.link to original article link to PMC article PubMed
CheckMate 511: Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. Epub 2019 Feb 27. link to original article link to PMC article contains dosing details in abstract PubMed NCT02714218

Nivolumab monotherapy

Regimen variant #1, q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Robert et al. 2014 (CheckMate 066)	2013-01 to 2014-02	Phase 3 (E-RT-switch-ooc)	Dacarbazine	Superior OS¹ (primary endpoint) OS60: 39% vs 17% (HR 0.50, 95% CI 0.40-0.63)
Larkin et al. 2015 (CheckMate 067)	2013-07 to 2014-03	Phase 3 (E-switch-ic)	1. Ipilimumab	Superior OS² (co-primary endpoint) Median OS: 36.9 vs 19.9 mo (HR 0.53, 95% CI 0.44-0.64)	Equivalent HRQoL
Larkin et al. 2015 (CheckMate 067)	2013-07 to 2014-03	Phase 3 (E-switch-ic)	2. Ipilimumab & Nivolumab	Inferior PFS (co-primary endpoint)	Equivalent HRQoL

¹Reported efficacy for CheckMate 066 is based on the 2020 update.
²Reported efficacy for CheckMate 067 is based on the 2021 update.
Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

Regimen variant #2, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Diab et al. 2023 (PIVOT IO 001)	2018-10-10 to 2021-12-17	Phase 3 (C)	Bempegaldesleukin	Seems to have superior ORR (co-primary endpoint) Did not meet co-primary endpoint of PFS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

Nivolumab (Opdivo) 360 mg IV once on day 1

21-day cycles

Regimen variant #3, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tawbi et al. 2022 (RELATIVITY-047)	2018-2020	Phase 2/3 (C)	Nivolumab & Relatlimab	Inferior PFS

Immunotherapy

Nivolumab (Opdivo) 480 mg IV once on day 1

28-day cycles

References

CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains dosing details in manuscript PubMed NCT01721772
1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
2. Update: Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. link to original article link to PMC article PubMed
CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01844505
1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article link to PMC article PubMed
2. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. link to original article link to PMC article PubMed
3. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
4. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
5. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. link to original article link to PMC article PubMed
RELATIVITY-047: Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03470922
1. Update: Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. PubMed link to original article
PIVOT IO 001: Diab A, Gogas H, Sandhu S, Long GV, Ascierto PA, Larkin J, Sznol M, Franke F, Ciuleanu TE, Pereira C, Muñoz Couselo E, Bronzon Damian F, Schenker M, Perfetti A, Lebbe C, Quéreux G, Meier F, Curti BD, Rojas C, Arriaga Y, Yang H, Zhou M, Ravimohan S, Statkevich P, Tagliaferri MA, Khushalani NI. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results. J Clin Oncol. 2023 Oct 20;41(30):4756-4767. Epub 2023 Aug 31. link to original article contains dosing details in manuscript PubMed NCT03635983

Nivolumab & Relatlimab

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tawbi et al. 2022 (RELATIVITY-047)	2018-2020	Phase 2/3 (E-RT-esc)	Nivolumab	Superior PFS¹ (primary endpoint) Median PFS: 10.2 vs 4.6 mo (HR 0.78, 95% CI 0.64-0.94) Might have superior OS¹ (secondary endpoint) Median OS: NYR vs 34.1 mo (HR 0.80, 95% CI 0.64-1.01)

¹Reported efficacy is based on the 2023 update.

Immunotherapy

Nivolumab and relatlimab (Opdualag) 480/160 mg IV once on day 1

28-day cycles

References

RELATIVITY-047: Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03470922
1. Update: Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. PubMed link to original article

Pembrolizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chesney et al. 2022 (MASTERKEY-265)	2016-2018	Phase 3 (C)	T-VEC & Pembrolizumab	Might have inferior PFS Median PFS: 8.5 vs 14.3 mo (HR 1.16, 95% CI 0.96-1.41)
Gogas et al. 2020 (IMspire170)	2017-2019	Phase 3 (C)	Cobimetinib & Atezolizumab	Did not meet primary endpoint of PFS Median PFS: 5.7 vs 5.5 mo (HR 0.87, 95% CI 0.67-1.14)

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

IMspire170: Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Francesco Ferrucci P, Pigozzo J, Rutkowski P, Mackiewicz J, Rooney I, Voulgari A, Troutman S, Pitcher B, Guo Y, Yan Y, Castro M, Mulla S, Flaherty K, Arance A. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021 Mar;32(3):384-394. Epub 2020 Dec 10. link to original article contains dosing details in manuscript PubMed NCT03273153
MASTERKEY-265: Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. Epub 2022 Aug 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02263508

Temozolomide & Bevacizumab

TB: Temozolomide & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kottschade et al. 2013 (N0775)	2008-2010	Randomized Phase 2 (E-de-esc)	ABC	Seems to have inferior PFS6 (primary endpoint)

Chemotherapy

Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5

Targeted therapy

Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

28-day cycles

References

N0775: Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00626405

Maintenance after first-line therapy

IL-2 & GM-CSF

Example orders

Example orders for IL-2 maintenance biotherapy in melanoma

Regimen

Study	Dates of enrollment	Evidence
O'Day et al. 2002	1998-2000	Phase 2

Note: timing below is based on the assumption that all cycles begin on a Monday.

Preceding treatment

Induction biochemotherapy

Immunotherapy, low-dose portion (cycles 1, 4, 7, 9, 11)

IL-2 - Aldesleukin (Proleukin) 1,000,000 units/m² SC once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26

Growth factor therapy, low-dose portion (cycles 1, 4, 7, 9, 11)

Sargramostim (Leukine) 125 mcg/m² SC once per day on days 1 to 14

Immunotherapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)

IL-2 - Aldesleukin (Proleukin) 18,000,000 units/m² IV continuous infusion over 6 hours, started on day 1, then 18,000,000 units/m² IV continuous infusion over 12 hours, then 18,000,000 units/m² IV continuous infusion over 24 hours, then 1,000,000 units/m² SC once per day on days 3 to 5, 8 to 12, 15 to 19, 22 to 26

Growth factor therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)

Sargramostim (Leukine) 125 mcg/m² SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)

Supportive therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)

One of the following 5-HT3 agonists:
- Ondansetron (Zofran) 32 mg IV once per day
- Granisetron 2 mg IV once per day
Omeprazole (Prilosec) 20 mg PO once every evening
Acetaminophen (Tylenol) 650 mg PO once every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
Meperidine (Demerol) 25 mg IV once every 6 hours as needed for chills and rigors

28-day cycle for 12 cycles

References

O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. link to original article contains dosing details in manuscript PubMed

Metastatic or unresectable disease, second-line

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, AUC 2/100

Study	Evidence
Rao et al. 2006	Retrospective

Chemotherapy

Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15
Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, AUC 6/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2015 (CheckMate 037)	2012-2014	Phase 3 (C)	Nivolumab	Inferior ORR

Note: this study did not meet the co-primary endpoint of OS.

Prior treatment criteria

CheckMate 037, BRAF WT: Exposure to ipilimumab
CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor

Chemotherapy

Carboplatin (Paraplatin) AUC 6 IV once on day 1
Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

Regimen variant #3, AUC 6/225 x 4, then AUC 5/175

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hauschild et al. 2009 (Bayer 11718)	2005-05 to 2006-05	Phase 3 (C)	CP & Sorafenib	Did not meet primary endpoint of PFS
Flaherty et al. 2013 (ECOG E2603)	2005-2008	Phase 3 (C)	CP & Sorafenib	Did not meet primary endpoint of OS
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (C)	1. Pembrolizumab; 2 mg/kg q3wk 2. Pembrolizumab; 10 mg/kg q3wk	Inferior PFS

Prior treatment criteria

Bayer 11718: Exposure to a dacarbazine- or temozolomide-containing regimen
ECOG E2603: No chemotherapy or MAP kinase pathway–targeted drugs

Chemotherapy

Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
- Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, given second
Paclitaxel (Taxol) as follows:
- Cycles 1 to 4: 225 mg/m² IV over 3 hours once on day 1, given first
- Cycle 5 up to 10: 175 mg/m² IV over 3 hours once on day 1, given first

21-day cycle for up to 10 cycles

Regimen variant #4, 200/100, 6 out of 8 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zimpfer-Rechner et al. 2003	1998-2000	Randomized Phase 2 (E-esc)	Paclitaxel	Did not meet primary efficacy endpoints

Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

Carboplatin (Paraplatin) 200 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36
Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

8-week cycles

References

Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. link to original article contains dosing details in abstract PubMed
Retrospective: Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article PubMed
Bayer 11718: Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. link to original article contains dosing details in manuscript PubMed NCT00111007
CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article contains dosing details in abstract PubMed NCT01721746
1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article link to PMC article PubMed
KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in supplement link to PMC article PubMed NCT01704287
1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

Carboplatin & nab-Paclitaxel

Regimen

Study	Dates of enrollment	Evidence
Kottschade et al. 2011 (N057E1)	2006-2007	Phase 2

Chemotherapy

Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, given second
Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

Supportive therapy

"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."

28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion

References

N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00404235

Lifileucel & IL-2

TILs: Tumor Infiltrating Lymphocytes

Regimen

Study	Dates of enrollment	Evidence
Sarnaik et al. 2021 (C-144-01)	2017-2019	Phase 2

Preceding treatment

FC lymphodepletion

Immunotherapy

Lifileuecel (Contego) administered 24 hours after last dose of fludarabine
IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV over 15 minutes every 8 to 12 hours as tolerated for up to 6 doses, starting 3 to 24 hours after completing lifileucel infusion

References

C-144-01: Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. Epub 2021 May 12. Erratum in: J Clin Oncol. 2021 Sep 10;39(26):2972. link to original article link to PMC article PubMed NCT02360579

Toripalimab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Awaiting publication (Junshi-JS001-BJZL-II)	2016-NR	Phase 2

Immunotherapy

Toripalimab (Loqtorzi) 3 mg/kg IV once on day 1

14-day cycles

References

Junshi-JS001-BJZL-II: contains dosing details on CT.gov NCT03013101

Metastatic or unresectable disease

Note: these regimens have not yet been classified by line of treatment.

Dacarbazine monotherapy

Example orders

Example orders for Dacarbazine (DTIC) in melanoma

Regimen variant #1, 850 mg/m² q3wk

Study	Dates of enrollment	Evidence
Pritchard et al. 1980	NR in abstract	Phase 2

Chemotherapy

Dacarbazine (DTIC) 850 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen variant #2, 1000 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Patel et al. 2011 (EORTC 18032)	2004-2007	Phase 3 (C)	Temozolomide	Did not meet primary endpoint of OS
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (C)	1. Pembrolizumab; 2 mg/kg q3wk 2. Pembrolizumab; 10 mg/kg q3wk	Inferior PFS
Weber et al. 2015 (CheckMate 037)	2012-2014	Phase 3 (C)	Nivolumab	Inferior ORR

Note: CheckMate 037 did not meet the co-primary endpoint of OS.

Prior treatment criteria

CheckMate 037, BRAF WT: Exposure to ipilimumab
CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor

Chemotherapy

Dacarbazine (DTIC) 1000 mg/m² IV once on day 1

21-day cycles

Regimen variant #3, 1250 mg/m², split doses, q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cocconi et al. 1992	1983-1988	Phase 3 (C)	Dacarbazine & Tamoxifen	Seems to have inferior OS

Prior treatment criteria

Cocconi et al. 1992: No previous treatment with dacarbazine or tamoxifen

Chemotherapy

Dacarbazine (DTIC) 250 mg/m² IV over 20 to 30 minutes once per day on days 1 to 5

21-day cycles

Regimen variant #4, 2500 mg/m², split doses, q4wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Luikart et al. 1984	NR	Phase 3 (C)	BVP	Did not meet efficacy endpoints

Note: This is the first phase 3 RCT published in the Journal of Clinical Oncology.

Chemotherapy

Dacarbazine (DTIC) 250 mg/m² IV once per day on days 1 to 10

28-day cycles

References

Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article contains dosing details in manuscript PubMed
Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains dosing details in manuscript PubMed
EORTC 18032: Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; EORTC Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. link to original article contains dosing details in abstract PubMed NCT00091572
CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed NCT01721746
1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article link to PMC article PubMed
KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in supplement link to PMC article PubMed NCT01704287
1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

Docetaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence
Aamdal et al. 1994	NR	Phase 2

Chemotherapy

Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

Supportive therapy

"No prophylactic treatment with steroids or antihistamines was given."

21-day cycles

References

Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J; EORTC Early Clinical Trials Group. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. link to original article contains dosing details in abstract PubMed

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

Example orders for High-dose (HD) IL-2 in melanoma

Regimen variant #1, 600k, up to 3 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sparano et al. 1993	NR	Phase 3 (C)	HD IL-2 & IFN alfa-2a	Did not meet primary endpoint of OS50%

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 28 total doses per cycle)

Supportive therapy

Included:
Acetaminophen (Tylenol)
Indomethacin (Indocin)
Meperidine (Demerol)
Ranitidine (Zantac)
Cimetidine (Tagamet)
Hydroxyzine (Atarax)
Diphenhydramine (Benadryl)
Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

12-week cycle for up to 3 cycles

Regimen variant #2, 600k, up to 5 cycles

Study	Dates of enrollment	Evidence
Atkins et al. 1999	1985-1993	Phase 2 (RT)

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
- After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above

Supportive therapy

Included:
Acetaminophen (Tylenol)
Indomethacin (Indocin)
Meperidine (Demerol)
Ranitidine (Zantac)
Cimetidine (Tagamet)
Hydroxyzine (Atarax)
Diphenhydramine (Benadryl)
Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

6- to 12-week cycle for up to 5 cycles

Regimen variant #3, 720k, up to 3 cycles

Study	Dates of enrollment	Evidence
Rosenberg et al. 1994	1985-1992	Non-randomized

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 30 total doses per cycle)

Supportive therapy

Included:
Acetaminophen (Tylenol)
Indomethacin (Indocin)
Meperidine (Demerol)
Ranitidine (Zantac)
Cimetidine (Tagamet)
Hydroxyzine (Atarax)
Diphenhydramine (Benadryl)
Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

2-month cycle for up to 3 cycles

Regimen variant #4, 720k, up to 5 cycles

Study	Dates of enrollment	Evidence
Atkins et al. 1999	1985-1993	Phase 2 (RT)

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
- After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above

Supportive therapy

Included:
Acetaminophen (Tylenol)
Indomethacin (Indocin)
Meperidine (Demerol)
Ranitidine (Zantac)
Cimetidine (Tagamet)
Hydroxyzine (Atarax)
Diphenhydramine (Benadryl)
Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

6- to 12-week cycle for up to 5 cycles

Regimen variant #5, 720k, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schwartzentruber et al. 2011 (NCI-2012-02897)	2000-2007	Phase 3 (C)	HD IL-2 & gp100 vaccine	Seems to have inferior clinical response

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours as tolerated on days 1 to 4, 22 to 25 (up to 24 total doses per cycle)

Supportive therapy

Included:
Acetaminophen (Tylenol)
Indomethacin (Indocin)
Meperidine (Demerol)
Ranitidine (Zantac)
Cimetidine (Tagamet)
Hydroxyzine (Atarax)
Diphenhydramine (Benadryl)
Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

7-week cycles

References

Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. link to original article contains dosing details in manuscript PubMed
Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article contains dosing details in manuscript PubMed
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. link to original article contains dosing details in manuscript PubMed
1. Update: Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. PubMed
NCI-2012-02897: Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011 Jun 2;364(22):2119-27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00019682

Ipilimumab monotherapy

Example orders

Example orders for Ipilimumab (Yervoy) in melanoma

Regimen variant #1, 3 mg/kg

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hodi et al. 2010 (MDX010-20)	2004-2008	Phase 3 (E-RT-switch-ooc)	1. Ipilimumab & gp100 peptide vaccine	Did not meet primary endpoint of OS
Hodi et al. 2010 (MDX010-20)	2004-2008	Phase 3 (E-RT-switch-ooc)	2. gp100 peptide vaccine	Superior OS (primary endpoint) Median OS: 10 vs 6.4 mo (HR 0.68, 95% CI 0.55-0.85)
Ascierto et al. 2017 (CA184-169)	2012-02-29 to 2012-07-09	Phase 3 (C)	Ipilimumab; 10 mg/kg	Seems to have inferior OS
Robert et al. 2015 (KEYNOTE-006)	2013-09-18 to 2014-03-03	Phase 3 (C)	1. Pembrolizumab; 10 mg/kg q2wks	Inferior OS
Robert et al. 2015 (KEYNOTE-006)	2013-09-18 to 2014-03-03	Phase 3 (C)	2. Pembrolizumab; 10 mg/kg q3wks	Inferior OS

Prior treatment criteria

KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease

Immunotherapy

Ipilimumab (Yervoy) 3 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles

Regimen variant #2, 10 mg/kg limited duration

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2008	2003-2005	Phase 1/2
Wolchok et al. 2010 (CA184-022)	2006-2007	Phase 2
Hodi et al. 2014 (ECOG E1608)	2010-2011	Randomized Phase 2 (C)	Ipilimumab & GM-CSF	Inferior OS
Ascierto et al. 2017 (CA184-169)	2012-02-29 to 2012-07-09	Phase 3 (E-esc)	Ipilimumab; 3 mg/kg	Seems to have superior OS¹ (primary endpoint) Median OS: 15.7 vs 11.5 mo (HR 0.84, 95% CI 0.71-0.99)

¹Reported efficacy is based on the 2020 update.
Note: In CA184-022, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.

Immunotherapy

Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles

Regimen variant #3, 10 mg/kg with maintenance

Study	Dates of enrollment	Evidence
O'Day et al. 2010 (CA184-008)	2006-2007	Phase 2
Margolin et al. 2012 (CA184-042)	2008-2009	Phase 2

Immunotherapy

Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles, then 12-week cycles

References

Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. link to original article PubMed
CA184-022: Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. link to original article contains dosing details in manuscript PubMed NCT00289640
MDX010-20: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00094653
1. HRQoL analysis: Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012 Jun 13;10:66. link to original article link to PMC article PubMed
2. Subgroup analysis: McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. link to original article PubMed
CA184-008: O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains dosing details in manuscript PubMed NCT00289627
CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains dosing details in abstract PubMed NCT00623766
ECOG E1608: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. link to original article link to PMC article contains dosing details in abstract PubMed NCT01134614
KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains dosing details in manuscript PubMed NCT01866319
1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
2. PRO analysis: Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. link to original article PubMed
3. Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
4. Update: Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. link to original article PubMed
CA184-169: Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. link to original article PubMed NCT01515189
1. Update: Ascierto PA, Del Vecchio M, Mackiewicz A, Robert C, Chiarion-Sileni V, Arance A, Lebbé C, Svane IM, McNeil C, Rutkowski P, Loquai C, Mortier L, Hamid O, Bastholt L, Dreno B, Schadendorf D, Garbe C, Nyakas M, Grob JJ, Thomas L, Liszkay G, Smylie M, Hoeller C, Ferraresi V, Grange F, Gutzmer R, Pikiel J, Hosein F, Simsek B, Maio M. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer. 2020 Jun;8(1):e000391. Erratum in: J Immunother Cancer. 2020 Jul;8(2). link to original article link to PMC article PubMed
M14TIL: NCT02278887

Ipilimumab & Nivolumab

Regimen

Study	Dates of enrollment	Evidence
Wolchok et al. 2013 (CheckMate 004)	2009-2013	Phase 1

Note: These doses were from the cohort deemed by CheckMate 004 as being "the maximum doses that were associated with an acceptable level of adverse events."

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1, given second
Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first

21-day cycle for 8 cycles

Subsequent treatment

Ipilimumab & nivolumab maintenance

References

CheckMate 004: Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. Epub 2013 Jun 2. link to original article contains dosing details in manuscript link to supplementary appendix link to PMC article PubMed NCT01024231

Ipilimumab-Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2016 (CheckMate 064)	2013-2014	Randomized Phase 2 (E-switch-ic)	Nivolumab, then Ipilimumab	Inferior OS (secondary endpoint)

Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1
Nivolumab (Opdivo) as follows:
- Cycle 5 onwards: 3 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 14-day cycles

References

CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01783938

Nivolumab monotherapy

Regimen variant #1, limited duration

Study	Dates of enrollment	Evidence
Weber et al. 2013 (MCC-15400)	2010-2012	Phase 1

Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data. It is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.

Immunotherapy

Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycle for 12 cycles, then 12-week cycle for 8 cycles (see note)

Regimen variant #2, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2015 (CheckMate 037)	2012-2014	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1a. Dacarbazine 1b. Carboplatin & Paclitaxel	Superior ORR (co-primary endpoint)

Note: CheckMate 037 did not meet the co-primary endpoint of OS. On 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Prior treatment criteria

CheckMate 037, BRAF WT: Exposure to ipilimumab
CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor

Immunotherapy

Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

References

MCC-15400: Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. Epub 2013 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01176461
CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed NCT01721746
1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article link to PMC article PubMed

Nivolumab-Ipilimumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Weber et al. 2016 (CheckMate 064)	2013-2014	Randomized Phase 2 (E-switch-ic)	Ipilimumab, then Nivolumab	Superior OS (secondary endpoint) Median OS: NYR vs 16.9 mo (HR 0.48, 95% CI 0.29-0.80)	Similar rate of grade 3-5 TRAEs (primary endpoint)

Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

Nivolumab (Opdivo) as follows:
- Cycles 1 to 6: 3 mg/kg IV once on day 1
- Cycle 11 onwards: 3 mg/kg IV once on day 1
Ipilimumab (Yervoy) as follows:
- Cycles 7 to 10: 3 mg/kg IV once on day 1

14-day cycle for 6 cycles, then 21-day cycle for 4 cycles, then 14-day cycles

References

CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01783938

Paclitaxel monotherapy

Example orders

Example orders for Paclitaxel (Taxol) in melanoma

Regimen variant #1, 80 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Day et al. 2013 (SYMMETRY)	2007-2009	Phase 3 (C)	Elesclomol & Paclitaxel	Did not meet primary endpoint of PFS
Hamid et al. 2014 (SUMMIT-1)	2009-NR	Phase 3 (C)	Tasisulam	Did not meet primary endpoint of OS

Note: This was the control arm of SYMMETRY, which was a negative study. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 175 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (C)	1. Pembrolizumab; 2 mg/kg q3wk 2. Pembrolizumab; 10 mg/kg q3wk	Inferior PFS

Chemotherapy

Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

Regimen variant #3, 250 mg/m² q3wk

Study	Dates of enrollment	Evidence
Legha et al. 1990	NR	Phase 2

Chemotherapy

Paclitaxel (Taxol) 250 mg/m² IV continuous infusion over 24 hours, started on day 1

21-day cycles

References

Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. link to original article contains dosing details in abstract PubMed
SYMMETRY: O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. link to original article contains dosing details in manuscript PubMed NCT00522834
SUMMIT-1: Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. link to original article contains dosing details in manuscript PubMed NCT01006252
KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01704287
1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

nab-Paclitaxel monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hersh et al. 2012	NR	Phase 2
Hersh et al. 2015 (CA033)	2009-04 to 2011-06	Phase 3 (E-switch-ic)	Dacarbazine	Seems to have superior PFS (primary endpoint) Median PFS: 4.8 vs 2.5 mo (HR 0.79, 95.1% CI 0.63-0.99)

Chemotherapy

Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Hersh et al. 2012	NR	Phase 2

Note: this dose was intended for previously treated patients.

Chemotherapy

Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. link to original article contains dosing details in abstract PubMed
CA033: Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00864253

Pembrolizumab monotherapy

Regimen variant #1, 2 mg/kg q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001_melanoma)	2011-2012	Phase 1, >20 pts
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (E-RT-switch-ooc)	Investigator's choice of: 1a. Carboplatin & Paclitaxel 1b. Dacarbazine 1c. Paclitaxel 1d. Temozolomide	Superior PFS (primary endpoint) PFS6: 34% vs 16% (HR 0.57, 95% CI 0.45-0.73)
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (E-RT-switch-ooc)	2. Pembrolizumab; 10 mg/kg q3wk	Did not meet primary endpoint of PFS

Prior treatment criteria

KEYNOTE-002, BRAFwt: Failure of ipilimumab
KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both

Immunotherapy

Pembrolizumab (Keytruda) 2 mg/kg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #2, 10 mg/kg q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001_melanoma)	2011-2012	Phase 1, >20 pts
Robert et al. 2015 (KEYNOTE-006)	2013-09-18 to 2014-03-03	Phase 3 (E-RT-switch-ic)	1. Ipilimumab	Superior OS (co-primary endpoint) OS12: 74.1% vs 58.2% (HR 0.63, 95% CI 0.47-0.83)
Robert et al. 2015 (KEYNOTE-006)	2013-09-18 to 2014-03-03	Phase 3 (E-RT-switch-ic)	2. Pembrolizumab; 10 mg/kg q3wk	Did not meet co-primary endpoints of PFS/OS

Prior treatment criteria

KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease

Immunotherapy

Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1

14-day cycles

Regimen variant #3, 10 mg/kg q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001_melanoma)	2011-2012	Phase 1, >20 pts
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (E-RT-switch-ooc)	Investigator's choice of: 1a. Carboplatin & Paclitaxel 1b. Dacarbazine 1c. Paclitaxel 1d. Temozolomide	Superior PFS (primary endpoint) PFS6: 38% vs 16% (HR 0.50, 95% CI 0.39-0.64)
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (E-RT-switch-ooc)	2. Pembrolizumab; 2 mg/kg	Did not meet primary endpoint of PFS
Robert et al. 2015 (KEYNOTE-006)	2013-09-18 to 2014-03-03	Phase 3 (E-RT-switch-ic)	1. Ipilimumab	Superior OS (co-primary endpoint) OS12: 68.4% vs 58.2% (HR 0.69, 95% CI 0.52-0.90)
Robert et al. 2015 (KEYNOTE-006)	2013-09-18 to 2014-03-03	Phase 3 (E-RT-switch-ic)	2. Pembrolizumab; 10 mg/kg q2wk	Did not meet co-primary endpoints of PFS/OS

Prior treatment criteria

KEYNOTE-002, BRAFwt: Failure of ipilimumab
KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both
KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease

Immunotherapy

Pembrolizumab (Keytruda) 10 mg/kg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #4, 200 mg q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Long et al. 2019 (ECHO-301/KEYNOTE-252)	2016-06-21 to 2017-08-07	Phase 3 (C)	Epacadostat & Pembrolizumab	Did not meet co-primary endpoints of PFS/OS

Prior treatment criteria

ECHO-301/KEYNOTE-252: No previous treatment with PD-1 or PD-L1 checkpoint inhibitors

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for up to 35 cycles (2 years)

References

KEYNOTE-001_melanoma: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. link to original article link to PMC article PubMed NCT01295827
1. Update: Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. link to original article contains dosing details in manuscript PubMed
2. Update: Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. link to original article PubMed
3. Update: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. link to original article link to PMC article PubMed
KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01704287
1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed
KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains dosing details in manuscript PubMed NCT01866319
1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
2. PRO analysis: Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. link to original article PubMed
3. Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
4. Update: Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. link to original article PubMed
ECHO-301/KEYNOTE-252: Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. link to original article contains dosing details in abstract PubMed NCT02752074

Temozolomide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Middleton et al. 2000b	1995-1997	Phase 3 (E-switch-ic)	Dacarbazine	Did not meet primary endpoint of OS
Kaufmann et al. 2005	1998-2001	Phase 3 (C)	Temozolomide & Interferon-alfa	Seems to have inferior ORR
Ribas et al. 2013 (A3671009)	2006-03 to 2007-07	Phase 3 (C)	Tremelimumab	Did not meet primary endpoint of OS
Ribas et al. 2015 (KEYNOTE-002)	2012-11-30 to 2013-11-13	Randomized Phase 2 (C)	1. Pembrolizumab; 2 mg/kg q3wk 2. Pembrolizumab; 10 mg/kg q3wk	Inferior PFS

Chemotherapy

Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5, taken while fasting

28-day cycles

References

Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains dosing details in manuscript PubMed
Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. link to original article contains dosing details in abstract PubMed
A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00257205
KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in supplement link to PMC article PubMed NCT01704287
1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

@@ Line 1: / Line 1: @@
-{{#lst:Section editor transclusions|mel}}
+<span id="BackToTop"></span>
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
+[[#top|Back to Top]]
+</div>
+{{#lst:Editorial board transclusions|mel}}
 ''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Melanoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Melanoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
 <big>'''Note: some melanoma regimens can be found on dedicated pages:'''
@@ Line 8: / Line 12: @@
 *'''[[Uveal melanoma]]'''
 </big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 15: / Line 18: @@
 |}
 {{TOC limit|limit=3}}
 =Guidelines=
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 ==ASCO==
+*'''2022:''' Seth et al. [https://doi.org/10.1200/jco.22.00944 Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update] [https://www.ncbi.nlm.nih.gov/pubmed/35658488 PubMed]
-*'''2020:''' Seth et al. [https://doi.org/10.1200/jco.20.00198 Systemic Therapy for Melanoma: ASCO Guideline]
+**'''2020:''' Seth et al. [https://doi.org/10.1200/jco.20.00198 Systemic Therapy for Melanoma: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/32228358 PubMed]
 ==EDF/EADO/EORTC==
+*'''2016:''' Garbe et al. [https://doi.org/10.1016/j.ejca.2016.05.005 Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016] [https://www.ncbi.nlm.nih.gov/pubmed/27367293 PubMed]
+==[https://www.esmo.org/ ESMO]==
+*'''2020:''' Keilholz et al. [https://doi.org/10.1016/j.annonc.2020.07.004 ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee] [https://www.ncbi.nlm.nih.gov/pubmed/32763453 PubMed]
+*'''2020:''' Michielin et al. [https://doi.org/10.1016/j.annonc.2020.07.005 ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee]  [https://www.ncbi.nlm.nih.gov/pubmed/32763452 PubMed]
-*'''2016:''' Garbe et al. [https://www.ejcancer.com/article/S0959-8049(16)32136-0/fulltext Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016] [https://pubmed.ncbi.nlm.nih.gov/27367293 PubMed]
+*'''2019:''' Michielin et al. [https://academic.oup.com/annonc/article/30/12/1884/5578477 Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/31566661 PubMed]
+**'''2015:''' Dummer et al. [http://annonc.oxfordjournals.org/content/26/suppl_5/v126.full.pdf+html Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/26314774/ PubMed]
-==[http://www.esmo.org/ ESMO]==
+**'''2012:''' Dummer et al. [https://doi.org/10.1093/annonc/mds229 Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997461/ PubMed]
+**'''2010:''' Dummer et al. [https://doi.org/10.1093/annonc/mdq188 Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555080/ PubMed]
-*'''2020:''' Keilholz et al. [https://doi.org/10.1016/j.annonc.2020.07.004 ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee]
+**'''2009:''' Dummer et al. [https://doi.org/10.1093/annonc/mdp152 Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454433/ PubMed]
-*'''2020:''' Michielin et al. [https://doi.org/10.1016/j.annonc.2020.07.005 ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee]
+**'''2008:''' Dummer et al. [https://doi.org/10.1093/annonc/mdn100 Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456782/ PubMed]
+**'''2007:''' Jost. [https://doi.org/10.1093/annonc/mdm045 Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491056/ PubMed]
-===Older===
+**'''2005:''' Jost et al. [https://doi.org/10.1093/annonc/mdi809 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma] [https://pubmed.ncbi.nlm.nih.gov/15888761/ PubMed]
+**'''2003:''' Jost. [https://doi.org/10.1093/annonc/mdg294 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma] [https://pubmed.ncbi.nlm.nih.gov/12853340/ PubMed]
-*'''2019:''' Michielin et al. [https://academic.oup.com/annonc/article/30/12/1884/5578477 Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
-*'''2015:''' Dummer et al. [http://annonc.oxfordjournals.org/content/26/suppl_5/v126.full.pdf+html Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/26314774 PubMed]
 ==[https://melanoma-inc.org/ INMC]==
+*'''2019:''' Amaria et al. [https://doi.org/10.1016/S1470-2045(19)30332-8 Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium] [https://www.ncbi.nlm.nih.gov/pubmed/31267972 PubMed]
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492 NCCN Guidelines - Melanoma: Cutaneous]
+**'''2019:''' Coit et al. [https://doi.org/10.6004/Jnccn.2019.0018 Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/30959471/ PubMed]
+**'''2016:''' Coit et al. [https://doi.org/10.6004/Jnccn.2016.0051 Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/27059193/ PubMed]
+**'''2014:''' Coit et al. [https://doi.org/10.6004/jnccn.2014.0066 Melanoma, Version 4.2014] [https://pubmed.ncbi.nlm.nih.gov/24812131/ PubMed]
+**'''2013:''' Coit et al. [https://doi.org/10.6004/Jnccn.2013.0055 Melanoma, version 2.2013: featured updates to the NCCN guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23584343/ PubMed]
+**'''2012:''' Coit et al. [https://doi.org/10.6004/Jnccn.2012.0036 Melanoma.] [https://pubmed.ncbi.nlm.nih.gov/22393197/ PubMed]
+**'''2012:''' Pfister et al. [https://doi.org/10.6004/Jnccn.2012.0033 Mucosal melanoma of the head and neck.] [https://pubmed.ncbi.nlm.nih.gov/22393194/ PubMed]
+**'''2009:''' Coit et al. [https://doi.org/10.6004/Jnccn.2009.0020 Melanoma.] [https://pubmed.ncbi.nlm.nih.gov/19401060/ PubMed]
+**'''2006:''' Houghton et al. [https://doi.org/10.6004/Jnccn.2006.0057 Melanoma.] [https://pubmed.ncbi.nlm.nih.gov/16884669/ PubMed]
+**'''2004:''' Author not listed. [https://doi.org/10.6004/Jnccn.2004.0003 Melanoma. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19777694/ PubMed]
-*'''2019:''' Amaria et al. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30332-8/fulltext Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium]
+==SITC==
+*'''2018:''' Sullivan et al. [http://dx.doi.org/10.1186/s40425-018-0362-6 An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0] [https://pubmed.ncbi.nlm.nih.gov/29848375/ PubMed]
+**'''2013:''' Kaufman et al. [https://doi.org/10.1038/nrclinonc.2013.153 The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma] [https://pubmed.ncbi.nlm.nih.gov/23982524/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+=Perioperative therapy=
+''This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.''
-*[https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf NCCN Guidelines - Cutaneous Melanoma]
+==Pembrolizumab monotherapy {{#subobject:0a3e71|Regimen=1}}==
+<div class="toccolours" style="background-color:#c8a2c8">
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa2211437 Patel et al 2023 (SWOG S1801)]
+|2019-02 to 2022-05
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|Adjuvant [[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
+| style="background-color:#1a9850" |Superior EFS (primary endpoint)<br>EFS24: 72% vs 49%<br>(HR 0.59, 95% CI 0.40-0.86)
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Resectable stage IIIB to IV melanoma without brain metastasis
+</div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Neoadjuvant {{#subobject:bd92fe|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for 3 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Definitive===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
+*[[Surgery#Surgical_resection|Complete resection]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Adjuvant===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for 15 cycles'''
+</div></div></div>
+===References===
+#'''SWOG S1801:''' Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. [https://doi.org/10.1056/NEJMoa2211437 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36856617/ PubMed] [https://clinicaltrials.gov/study/NCT03698019 NCT03698019]
 =Neoadjuvant response criteria=
 *'''2018:''' Tetzlaff et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096739/ Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma]
 =Adjuvant therapy=
 ==Cisplatin & Temozolomide {{#subobject:63gh1g|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:1jizga|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 63: / Line 119: @@
 | rowspan="2" |[https://doi.org/10.1158/1078-0432.ccr-13-0739 Lian et al. 2013]
 | rowspan="2" |2007-2009
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
-| style="background-color:#1a9850" |Superior RFS
+| style="background-color:#1a9850" |Superior RFS (co-primary endpoint)
 |-
 |2. [[Melanoma_-_null_regimens#Observation|Observation]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Melanoma_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
 *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup>/day PO on days 1 to 5
 '''21-day cycle for 6 cycles'''
+</div></div>
 ===References===
+#Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. [https://doi.org/10.1158/1078-0432.ccr-13-0739 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23833309/ PubMed] ChiCTR-TRC-11001798
-#Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. [https://doi.org/10.1158/1078-0432.ccr-13-0739 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23833309/ PubMed] ChiCTR-TRC-11001798
 ==Ipilimumab monotherapy {{#subobject:89bbc6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 ===Example orders===
 *[[Example orders for Ipilimumab (Yervoy) in melanoma]]
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 3 mg/kg x 1 year {{#subobject:f9bac45|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1200/JCO.19.01381 Tarhini et al. 2019 (ECOG E1609)]
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030886/ Tarhini et al. 2019 (ECOG E1609)]
 | rowspan="2" |2011-2014
 | rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
+|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#91cf60" |Seems to have superior OS (co-primary endpoint)<br>OS60: 72% vs 67%<br>(HR 0.78, 95.6% CI 0.61-0.99)
 |-
-|[[#Ipilimumab_monotherapy|Ipilimumab]]; 10 mg/kg
+|2. [[#Ipilimumab_monotherapy|Ipilimumab]]; 10 mg/kg
 | style="background-color:#d3d3d3" |Not reported
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Stage IIIB, IIIC, or IV melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Surgical_resection|Complete resection]]
-*[[Surgery#Surgical_resection|Complete resection]] of stage IIIB, IIIC, or IV melanoma
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1
+'''21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles'''
-'''3-week cycle for 4 cycles, then 12-week cycle for up to 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 10 mg/kg x 1 year {{#subobject:f92245|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!12-month recurrence-free survival (RFS)
-!Comparator RFS
 |-
-| rowspan="2" |[https://doi.org/10.1200/JCO.19.01381 Tarhini et al. 2019 (ECOG E1609)]
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030886/ Tarhini et al. 2019 (ECOG E1609)]
 | rowspan="2" |2011-2014
 | rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
+|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
-|
-|
 |-
-|[[#Ipilimumab_monotherapy|Ipilimumab]]; 3 mg/kg
+|2. [[#Ipilimumab_monotherapy|Ipilimumab]]; 3 mg/kg
 | style="background-color:#d3d3d3" |Not reported
-|
-|
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1709030 Weber et al. 2017 (Checkmate 238)]
+|[https://doi.org/10.1056/NEJMoa1709030 Weber et al. 2017 (CheckMate 238)]
-|2015
+|2015-03-30 to 2015-11-30
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[Melanoma#Nivolumab_monotherapy|Nivolumab]]
 | style="background-color:#d73027" |Inferior RFS
-|61% overall<br>Stage IIIB or IIIC: 62% (95% CI: 56-66.5)<br>Stage IV: 57.5% (95% CI: 46-67)
-|70.5% overall<br>Stage IIIB or IIIC: 72% (95% CI, 67-77)<br>Stage IV: 63% (95% CI, 52-72.5)
 |-
 |}
+''Note: 12-month recurrence-free survival (RFS) in this arm of CheckMate 238 was 61% overall; Stage IIIB or IIIC: 62% (95% CI: 56-66.5); Stage IV: 57.5% (95% CI: 46-67). In the experimental arm, it was 70.5% overall; Stage IIIB or IIIC: 72% (95% CI, 67-77); Stage IV: 63% (95% CI, 52-72.5).''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Stage IIIB, IIIC, or IV melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Surgical_resection|Complete resection]]
-*[[Surgery#Surgical_resection|Complete resection]] of stage IIIB, IIIC, or IV melanoma
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
+'''21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles'''
-'''3-week cycle for 4 cycles, then 12-week cycle for up to 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 3 years {{#subobject:a17a88|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 171: / Line 222: @@
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 17%" |Study
-! style="width: 15%" |Years of enrollment
+! style="width: 15%" |Dates of enrollment
 ! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 17%" |Comparator
@@ Line 177: / Line 228: @@
 ! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/fulltext Eggermont et al. 2015 (EORTC 18071)]
+|[https://doi.org/10.1016/S1470-2045(15)70122-1 Eggermont et al. 2015 (EORTC 18071)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-76-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
 |2008-2011
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Melanoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.73, 95% CI 0.60-0.89)
+| style="background-color:#1a9850" |Superior RFS<sup>1</sup> (primary endpoint)<br>RFS60: 40.8% vs 30.3%<br>(HR 0.76, 95% CI 0.64-0.89)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 65.4% vs 54.4%<br>(HR 0.72, 95.1% CI 0.58-0.88)
 | style="background-color:#eeee01" |Similar HRQoL<sup>2</sup>
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
+''<sup>1</sup>Reported efficacy is based on the 2016 update.''<br>
-''<sup>2</sup>While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinically relevance.''
+''<sup>2</sup>While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinical relevance.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Stage III cutaneous melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Surgical_resection|Complete resection]]
-*[[Surgery#Surgical_resection|Complete resection]] of stage III cutaneous melanoma
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
 '''21-day cycle for 4 cycles, then 12-week cycle for 12 cycles (3 years)'''
+</div></div>
 ===References===
+#'''EORTC 18071:''' Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Karra Gurunath R, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Epub 2015 Mar 31. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. [https://doi.org/10.1016/S1470-2045(15)70122-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25840693/ PubMed] [https://clinicaltrials.gov/study/NCT00636168 NCT00636168]
-#'''EORTC 18071:''' Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Karra Gurunath R, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25840693 PubMed] NCT00636168
+##'''Update:''' Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. [https://doi.org/10.1056/NEJMoa1611299 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5648545/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27717298/ PubMed]
-##'''Update:''' Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611299 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27717298 PubMed]
+##'''HRQoL analysis:''' Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. [https://doi.org/10.1016/s1470-2045(17)30015-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636622/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28162999/ PubMed]
-##'''HRQoL analysis:''' Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. [https://doi.org/10.1016/s1470-2045(17)30015-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636622/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28162999 PubMed]
+##'''Update:''' Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. [https://doi.org/10.1016/j.ejca.2019.07.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31400634/ PubMed]
-##'''Update:''' Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. [https://doi.org/10.1016/j.ejca.2019.07.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31400634 PubMed]
+#'''CheckMate 238:''' Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. [https://doi.org/10.1056/NEJMoa1709030 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28891423/ PubMed] [https://clinicaltrials.gov/study/NCT02388906 NCT02388906]
-#'''CheckMate 238:''' Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709030 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28891423 PubMed] NCT02388906
+##'''Update:''' Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. [https://doi.org/10.1016/s1470-2045(20)30494-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32961119/ PubMed]
-##'''Update:''' Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. [https://doi.org/10.1016/s1470-2045(20)30494-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32961119 PubMed]
+#'''ECOG E1609:''' Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. [https://doi.org/10.1200/JCO.19.01381 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030886/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31880964/ PubMed] [https://clinicaltrials.gov/study/NCT01274338 NCT01274338]
-#'''ECOG E1609:''' Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. [https://doi.org/10.1200/JCO.19.01381 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31880964 PubMed] NCT01274338
+##'''HRQoL analysis:''' McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. Epub 2022 Aug 27. [https://doi.org/10.1007/s11136-022-03226-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839512/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36029412/ PubMed]
-#'''SWOG S1404:''' NCT02506153
+#'''SWOG S1404:''' Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. [https://doi.org/10.1158/2159-8290.cd-21-1141 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34764195/ PubMed] [https://clinicaltrials.gov/study/NCT02506153 NCT02506153]
+##'''HRQoL analysis:''' Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. [https://doi.org/10.1001/jamaoncol.2022.5486 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9685550/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36416836/ PubMed]
 ==Ipilimumab & Nivolumab {{#subobject:28103f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen variant #1 {{#subobject:6cf5ae|Variant=1}}===
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:6cf5ae|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 223: / Line 280: @@
 | rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30417-7 Zimmer et al. 2020 (IMMUNED)]
 | rowspan="2" |2015-2018
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |1. [[#Nivolumab_monotherapy|Nivolumab]]
 | style="background-color:#d3d3d3" |Not reported
 |-
 |2. [[Melanoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#1a9850" |Superior RFS<br>Median RFS: Not reached vs 6.4 mo<br>(HR 0.23, 97.5% CI 0.12-0.45)
+| style="background-color:#91cf60" |Superior RFS (primary endpoint)<br>Median RFS: NYR vs 12.4 mo<br>(HR 0.23, 97.5% CI 0.12-0.45)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.41, 95% CI 0.17-0.99)
 |-
 |}
+''<sup>1</sup>Reported efficacy is based on the 2022 update.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Stage IV melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Surgical_resection|Resection]] or definitive [[Regimen_classes#Radiotherapy-based_regimen|radiotherapy]], with NED
-*[[Surgery#Surgical_resection|Resection]] or radiotherapy of stage IV melanoma, with NED
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Ipilimumab (Yervoy)]] as follows:
 **Cycles 1 to 4: 3 mg/kg IV once on day 1
@@ Line 242: / Line 304: @@
 **Cycles 1 to 4: 1 mg/kg IV once on day 1,
 **Cycles 5 to 24: 3 mg/kg IV once on day 1
 '''21-day cycle for 4 cycles, then 14-day cycle for 20 cycles (1 year)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:jg8cxe|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ Weber et al. 2022 (CheckMate 915)]
+|2017-04 to 2018-06
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Nivolumab_monotherapy|Nivolumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br>RFS24: 64.6% vs 63.2%<br>(HR 0.92, 97.295% CI 0.77-1.09)
+|-
+|}
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority in this setting.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*Stage IIIB, IIIC, IIID, or IV melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Surgical_resection|Complete resection]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1
+*[[Nivolumab (Opdivo)]] 240 mg IV once per day on days 1, 15, 29
+'''42-day cycle for 9 cycles (1 year)'''
+</div></div>
 ===References===
+#'''IMMUNED:''' Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. [https://doi.org/10.1016/s0140-6736(20)30417-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416781/ PubMed] [https://clinicaltrials.gov/study/NCT02523313 NCT02523313]
-#'''IMMUNED:''' Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. [https://doi.org/10.1016/s0140-6736(20)30417-7 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416781 PubMed] NCT02523313
+##'''Update:''' Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet. 2022 Oct 1;400(10358):1117-1129. Epub 2022 Sep 10. [https://doi.org/10.1016/s0140-6736(22)01654-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36099927/ PubMed]
+#'''CheckMate 915:''' Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. [https://doi.org/10.1200/jco.22.00533 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36162037/ PubMed] [https://clinicaltrials.gov/study/NCT03068455 NCT03068455]
 ==Nivolumab monotherapy {{#subobject:2b3899|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen variant #1, 240 mg flat dose {{#subobject:igj2d5|Variant=1}}===
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a228d5|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!12-month recurrence-free survival (RFS)
-!Comparator RFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1709030 Weber et al. 2017 (Checkmate 238)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ Weber et al. 2022 (CheckMate 915)]
-|2015
+|2017-04 to 2018-06
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Melanoma#Ipilimumab_monotherapy|Ipilimumab]]
+|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
-| style="background-color:#1a9850" |Superior RFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
-|71% overall<br>Stage IIIB or IIIC: 72.3% (95% CI, 67 to 77)<br>Stage IV: 63.0% (95% CI, 52 to 73)
-|61% overall<br>Stage IIIB or IIIC: 61.6% (95% CI, 56 to 66.5)<br>Stage IV: 57.5% (95% CI, 46 to 67)
 |-
-| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30417-7 Zimmer et al. 2020 (IMMUNED)]
+|}
-| rowspan="2" |2015-2018
+<div class="toccolours" style="background-color:#fdcdac">
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-esc)
+====Eligibility criteria====
-|1. [[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
+*Stage IIIB, IIIC, IIID, or IV melanoma
-| style="background-color:#d3d3d3" |Not reported
+</div>
-|
+<div class="toccolours" style="background-color:#cbd5e8">
-|
-|-
-|2. [[Melanoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#91cf60" |Seems to have superior RFS
-|52% (95% CI, 38 to 64)
-|
-|-
-|}
 ====Preceding treatment====
+*[[Surgery#Surgical_resection|Complete resection]]
-*Checkmate 238: [[Surgery#Surgical_resection|Complete resection]] of stage IIIB, IIIC, or IV melanoma
+</div>
-*IMMUNED: [[Surgery#Surgical_resection|Resection]] or radiotherapy of stage IV melanoma, with NED
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 '''14-day cycle for up to 26 cycles (1 year)'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 480 mg flat dose {{#subobject:iy5335|Variant=1}}===
-#'''CheckMate 238:''' Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709030 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28891423 PubMed] NCT02388906
-##'''Update:''' Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. [https://doi.org/10.1016/s1470-2045(20)30494-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32961119 PubMed]
-#'''IMMUNED:''' Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. [https://doi.org/10.1016/s0140-6736(20)30417-7 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416781 PubMed] NCT02523313
-==Pembrolizumab monotherapy {{#subobject:0a3e71|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, adult dosing {{#subobject:bd92fe|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/10.1056/NEJMoa1802357 Eggermont et al. 2018 (EORTC 1325/KEYNOTE-054)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10667090/ Kirkwood et al. 2023 (CheckMate 76K)]
-|2015-2016
+|2019-10-28 to 2021-11-03
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Melanoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#1a9850" |Superior RFS<sup>1</sup><br>RFS42: 60% vs 41%<br>(HR 0.59, 99% CI 0.49-0.70)
+| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS12: 89 vs 79.4%<br>(HR 0.42, 95% CI 0.30-0.59)
-|-
-|Awaiting publication (KEYNOTE-716)
-|2018-NR
-| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[Melanoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#1a9850" |Superior RFS<sup>2</sup><br>Median RFS: NR vs NR<br>(HR 0.65, 95% CI 0.46-0.92)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
+<div class="toccolours" style="background-color:#fdcdac">
-''<sup>2</sup>Reported efficacy is from the FDA approval announcement.''
+====Eligibility criteria====
+*Stage IIB or IIC melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Surgical_resection|Complete resection]]
-*[[Surgery#Lymphadenectomy|Complete regional lymphadenectomy]], within 13 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''28-day cycle for 13 cycles (1 year)'''
+</div></div><br>
-'''21-day cycle for 18 cycles (1 year)'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, weight-based {{#subobject:a228d5|Variant=1}}===
-===Regimen variant #2, pediatric dosing {{#subobject:ug1xfe|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|Awaiting publication (KEYNOTE-716)
+|[https://doi.org/10.1056/NEJMoa1709030 Weber et al. 2017 (CheckMate 238)]
-|2018-NR
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-174-1 <span style="color:white;">ESMO-MCBS (C)</span>]'''
-|[[Melanoma_-_null_regimens#Placebo|Placebo]]
+|-
-| style="background-color:#1a9850" |Superior RFS<sup>1</sup><br>Median RFS: NR vs NR<br>(HR 0.65, 95% CI 0.46-0.92)
+|} -->
+|2015-03-30 to 2015-11-30
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|[[Melanoma#Ipilimumab_monotherapy|Ipilimumab]]
+| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS12: 70.5% vs 60.8%<br>(HR 0.65, 97.56% CI 0.51-0.83)
+|-
+| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30417-7 Zimmer et al. 2020 (IMMUNED)]
+| rowspan="2" |2015-2018
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|1. [[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|2. [[Melanoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>Median RFS: 12.4 vs 6.4 mo<br>(HR 0.56, 97.5% CI 0.33-0.94)
 |-
 |}
-''<sup>1</sup>Reported efficacy is from the FDA approval announcement.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*CheckMate 238: Stage IIIB, IIIC, or IV melanoma
+*IMMUNED: Stage IV melanoma
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*CheckMate 238: [[Surgery#Surgical_resection|Complete resection]]
-*[[Surgery#Lymphadenectomy|Complete regional lymphadenectomy]], within 13 weeks
+*IMMUNED: [[Surgery#Surgical_resection|Resection]] or definitive [[Regimen_classes#Radiotherapy-based_regimen|radiotherapy]], with NED
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+'''14-day cycle for up to 26 cycles (1 year)'''
+</div></div>
+===References===
+#'''CheckMate 238:''' Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. [https://doi.org/10.1056/NEJMoa1709030 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28891423/ PubMed] [https://clinicaltrials.gov/study/NCT02388906 NCT02388906]
+##'''Update:''' Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. [https://doi.org/10.1016/s1470-2045(20)30494-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32961119/ PubMed]
+#'''IMMUNED:''' Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. [https://doi.org/10.1016/s0140-6736(20)30417-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416781/ PubMed] [https://clinicaltrials.gov/study/NCT02523313 NCT02523313]
+#'''CheckMate 915:''' Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. [https://doi.org/10.1200/jco.22.00533 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36162037/ PubMed] [https://clinicaltrials.gov/study/NCT03068455 NCT03068455]
+#'''CheckMate 76K:''' Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, Long GV. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023 Nov;29(11):2835-2843. Epub 2023 Oct 16. Erratum in: Nat Med. 2023 Nov 3. [https://doi.org/10.1038/s41591-023-02583-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10667090/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37845511/ PubMed] [https://clinicaltrials.gov/study/NCT04099251 NCT04099251]
+#'''PIVOT-12:''' [https://clinicaltrials.gov/study/NCT04410445 NCT04410445]
-*[[Pembrolizumab (Keytruda)]] 2 mg/kg (maximum dose of 200 mg) IV once on day 1
+==Pembrolizumab monotherapy {{#subobject:0a3e71|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''21-day cycle for 18 cycles (1 year)'''
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
-===References===
-#'''EORTC 1325/KEYNOTE-054:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. [https://www.nejm.org/doi/10.1056/NEJMoa1802357 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29658430 PubMed] NCT02362594
-##'''Update:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. Epub 2020 Sep 18. [https://doi.org/10.1200/jco.20.02110 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676886/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32946353 PubMed]
-##'''Update:''' Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Apr 12:S1470-2045(21)00065-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(21)00065-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33857412/ PubMed]
-##'''HRQoL analysis:''' Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Apr 12:S1470-2045(21)00081-4. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(21)00081-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33857414/ PubMed]
-#'''KEYNOTE-716:''' NCT03553836
-=Local therapy=
-==Talimogene laherparepvec monotherapy {{#subobject:PYR1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
+===Regimen variant #1, adult dosing {{#subobject:bd92fe|Variant=1}}===
-===Regimen {{#subobject:PYV1|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2014.58.3377 Andtbacka et al. 2015 (OPTiM)]
+|[https://doi.org/10.1056/NEJMoa1802357 Eggermont et al. 2018 (KEYNOTE-054)]
-|2009-2011
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-173-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-|GM-CSF
+|-
-| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> <br>(HR 0.79, 95% CI 0.62-1.00)
+|} -->
+|2015-08 to 2016-11
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Melanoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#1a9850" |Superior RFS<sup>1</sup> (primary endpoint)<br>RFS60: 55.4% vs 38.3%<br>(HR 0.61, 95% CI 0.51-0.72)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904282/ Grossmann et al. 2022 (SWOG S1404)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|HD-Interferon alfa-2b]]<br>2. [[#Ipilimumab_monotherapy|Ipilimumab]]
+| style="background-color:#1a9850" |Superior RFS (co-primary endpoint)<br>(HR 0.77, 99.62% CI 0.59-0.99)
+|-
+|[https://doi.org/10.1016/s0140-6736(22)00562-1 Luke et al. 2022 (KEYNOTE-716)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-339-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 |-
-|}
+|} -->
-''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
+|2018-2020
-''Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.''
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-====Immunotherapy====
+|[[Melanoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#1a9850" |Superior RFS<sup>2</sup> (primary endpoint)<br>Median RFS: 37.2 mo vs NYR<br>(HR 0.64, 95% CI 0.50-0.84)
-*[[Talimogene laherparepvec (Imlygic)]] as follows:
+|-
-**Initially, to seroconvert HSV-seronegative patients: 1,000,000 pfu/mL SC intralesional injection once on day 1
+|[https://doi.org/10.1056/NEJMoa2211437 Patel et al 2023 (SWOG S1801)]
-**Thereafter: 100,000,000 pfu/mL SC intralesional injection once on day 1
+|2019-02 to 2022-05
-**Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."
+| style="background-color:#1a9851" |Phase 3 (C)
+|Perioperative [[#Pembrolizumab_monotherapy|Pembrolizumab]]
-'''21-day cycle for 1 cycle, then 14-day cycle for at least 12 cycles'''
+| style="background-color:#d73027" |Inferior EFS
-====Subsequent treatment====
+|-
+|[https://doi.org/10.1016/s0140-6736(23)02268-7 Weber et al. 2024 (KEYNOTE-942)]
-*Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months
+|2019-07-18 to 2021-09-30
+| style="background-color:#1a9851" |Phase 3 (C)
-===References===
+|[[#Pembrolizumab_.26_mRNA-4157_777|Pembrolizumab & mRNA-4157]]
-<!-- Presented in part at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013, and 50th ASCO Annual Meeting, Chicago, IL, May 30-June 3, 2014. -->
+| style="background-color:#fee08b" |Might have inferior RFS (primary endpoint)<br>RFS18: 62% vs 79%<br>(HR 1.78, 95% CI 0.98-3.24)
-#'''OPTiM:''' Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. [https://doi.org/10.1200/jco.2014.58.3377 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26014293 PubMed] NCT00769704
-##'''Update:''' Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. [https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0623-z link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554874/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31171039 PubMed]
-=Metastatic or unresectable disease, first-line=
-==ABC {{#subobject:ddf2d4|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-ABC: '''<u>A</u>'''braxane (Paclitaxel nanoparticle albumin-bound), '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin
+''<sup>1</sup>Reported efficacy for KEYNOTE-054 is based on the 2022 update.''<br>
+''<sup>2</sup>Reported efficacy for KEYNOTE-716 is based on the 2022 update.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Eligibility criteria====
+*KEYNOTE-942: completely resected stage IIIB to IV
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*KEYNOTE-716: [[Surgery#Lymphadenectomy|Complete regional lymphadenectomy]], within 13 weeks
+*SWOG S1404: [[Surgery#Surgical_resection|Complete resection]], within 14 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for 18 cycles (1 year)'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:318c66|Variant=1}}===
+===Regimen variant #2, pediatric dosing {{#subobject:ug1xfe|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)]
+|[https://doi.org/10.1016/s0140-6736(22)00562-1 Luke et al. 2022 (KEYNOTE-716)]
-|2008-2010
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-339-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-|[[#Temozolomide_.26_Bevacizumab|Temozolomide & Bevacizumab]]
+|-
-| style="background-color:#91cf60" |Seems to have superior PFS6
+|} -->
+|2018-2020
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Melanoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#1a9850" |Superior RFS<sup>2</sup> (primary endpoint)<br>Median RFS: 37.2 mo vs NYR<br>(HR 0.64, 95% CI 0.50-0.84)
 |-
 |}
-''The doses listed here are the amended starting doses.''
+''<sup>1</sup>Reported efficacy is based on the 2022 update.''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+*KEYNOTE-716: [[Surgery#Lymphadenectomy|Complete regional lymphadenectomy]], within 13 weeks
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 2 mg/kg (maximum dose of 200 mg) IV once on day 1
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
+'''21-day cycle for 18 cycles (1 year)'''
+</div></div>
-'''28-day cycles'''
 ===References===
-<!-- This study was presented at the American Society for Clinical Oncology 2011 Annual Meeting, June 3 to 7, Chicago, Illinois, as a poster discussion. -->
+#'''KEYNOTE-054:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. [https://doi.org/10.1056/NEJMoa1802357 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29658430/ PubMed] [https://clinicaltrials.gov/study/NCT02362594 NCT02362594]
+##'''Update:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. Epub 2020 Sep 18. [https://doi.org/10.1200/jco.20.02110 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676886/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32946353/ PubMed]
+##'''Update:''' Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):643-654. Epub 2021 Apr 12. [https://doi.org/10.1016/s1470-2045(21)00065-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33857412/ PubMed]
+##'''HRQoL analysis:''' Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):655-664. Epub 2021 Apr 12. [https://doi.org/10.1016/s1470-2045(21)00081-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33857414/ PubMed]
+##'''Update:''' Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Boers-Sonderen M, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Lorigan P, Grebennik D, Krepler C, Marreaud S, Suciu S, Robert C. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evid. 2022 Nov;1(11):EVIDoa2200214. Epub 2022 Sep 10. [https://doi.org/10.1056/EVIDoa2200214 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38319852/ PubMed]
+#'''KEYNOTE-716:''' Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, de la Cruz Merino L, Khattak MA, Schadendorf D, Long GV, Ascierto PA, Mandala M, De Galitiis F, Haydon A, Dummer R, Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer RA, Kirkwood JM, Chen K, Diede SJ, Ahsan S, Ibrahim N, Eggermont AMM; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729. Epub 2022 Apr 1. [https://doi.org/10.1016/s0140-6736(22)00562-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35367007/ PubMed] [https://clinicaltrials.gov/study/NCT03553836 NCT03553836]
+##'''HRQoL analysis:''' Khattak MA, Luke JJ, Long GV, Ascierto PA, Rutkowski P, Schadendorf D, Robert C, Grob JJ, de la Cruz Merino L, Del Vecchio M, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Carlino MS, Mohr P, De Galitiis F, Ross MI, Eroglu Z, Chen K, Jiang R, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Kirkwood JM. Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study. Eur J Cancer. 2022 Nov;176:207-217. Epub 2022 Oct 3. [https://doi.org/10.1016/j.ejca.2022.08.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36202690/ PubMed]
+##'''Update:''' Long GV, Luke JJ, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Mohr P, Dummer R, Gershenwald JE, Yoon CH, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Ascierto PA; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1378-1388. Epub 2022 Oct 18. [https://doi.org/10.1016/s1470-2045(22)00559-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36265502/ PubMed]
+##'''Update:''' Luke JJ, Ascierto PA, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Long GV. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol. 2024 May 10;42(14):1619-1624. Epub 2024 Mar 7. [https://doi.org/10.1200/jco.23.02355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38452313/ PubMed]
+#'''SWOG S1404:''' Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. [https://doi.org/10.1158/2159-8290.cd-21-1141 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34764195/ PubMed] [https://clinicaltrials.gov/study/NCT02506153 NCT02506153]
+##'''HRQoL analysis:''' Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. [https://doi.org/10.1001/jamaoncol.2022.5486 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9685550/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36416836/ PubMed]
+#'''SWOG S1801:''' Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. [https://doi.org/10.1056/NEJMoa2211437 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36856617/ PubMed] [https://clinicaltrials.gov/study/NCT03698019 NCT03698019]
+#'''KEYNOTE-942:''' Weber JS, Carlino MS, Khattak A, Meniawy T, Ansstas G, Taylor MH, Kim KB, McKean M, Long GV, Sullivan RJ, Faries M, Tran TT, Cowey CL, Pecora A, Shaheen M, Segar J, Medina T, Atkinson V, Gibney GT, Luke JJ, Thomas S, Buchbinder EI, Healy JA, Huang M, Morrissey M, Feldman I, Sehgal V, Robert-Tissot C, Hou P, Zhu L, Brown M, Aanur P, Meehan RS, Zaks T. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb 17;403(10427):632-644. Epub 2024 Jan 18. [https://doi.org/10.1016/s0140-6736(23)02268-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38246194/ PubMed] [https://clinicaltrials.gov/study/NCT03897881 NCT03897881]
-#'''N0775:''' Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.27760/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22915053 PubMed] NCT00626405
+=Local therapy=
+==Talimogene laherparepvec monotherapy {{#subobject:PYR1|Regimen=1}}==
-==Carboplatin & Paclitaxel (CP) {{#subobject:hbq571|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:PYV1|Variant=1}}===
-|-
-|[[#top|back to top]]
-|}
-CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel
-<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin
-===Regimen variant #1, 5/175 {{#subobject:6ahg7c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.20.00902 Yan et al. 2021 (BCH-MM-131101)]
+|[https://doi.org/10.1200/jco.2014.58.3377 Andtbacka et al. 2015 (OPTiM)]
-|2014-2017
+|2009-2011
-| style="background-color:#1a9851" |Randomized Phase II (C)
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
-|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|CP & Bevacizumab]]
+|[[Melanoma_-_historical#Sargramostim_monotherapy|GM-CSF]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+| style="background-color:#1a9850" |Superior DRR (primary endpoint)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>(HR 0.79, 95% CI 0.62-1.00)
 |-
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
+''Note: Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
+*[[Talimogene laherparepvec (Imlygic)]] as follows:
+**Initially, to seroconvert HSV-seronegative patients: 1,000,000 pfu/mL SC intralesional injection once on day 1
+**Thereafter: 100,000,000 pfu/mL SC intralesional injection once on day 1
+**Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."
+'''21-day course, then 14-day cycle for at least 12 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+====Subsequent treatment====
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
+*Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months
+</div></div>
+===References===
+<!-- Presented in part at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013, and 50th ASCO Annual Meeting, Chicago, IL, May 30-June 3, 2014. -->
+#'''OPTiM:''' Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. Epub 2015 May 26. [https://doi.org/10.1200/jco.2014.58.3377 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26014293/ PubMed] [https://clinicaltrials.gov/study/NCT00769704 NCT00769704]
+##'''Update:''' Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. [https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0623-z link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554874/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31171039/ PubMed]
-'''28-day cycles'''
+=Metastatic or unresectable disease, first-line=
+==ABC {{#subobject:ddf2d4|Regimen=1}}==
-===Regimen variant #2 {{#subobject:6a8ye2|Variant=1}}===
+ABC: '''<u>A</u>'''braxane (Paclitaxel nanoparticle albumin-bound), '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:318c66|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)]
-|2005-2008
+|2008-2010
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
+|[[#Temozolomide_.26_Bevacizumab|Temozolomide & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#91cf60" |Seems to have superior PFS6 (primary endpoint)
 |-
 |}
+''Note: The doses listed here are the amended starting doses.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Carboplatin (Paraplatin)]] as follows:
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
-**Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, '''given second'''
+====Targeted therapy====
-**Cycle 5 onwards: AUC 5 IV over 30 minutes once on day 1, '''given second'''
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
-*[[Paclitaxel (Taxol)]] as follows:
+'''28-day cycles'''
-**Cycles 1 to 4: 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+</div></div>
-**Cycle 5 onwards: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-'''21-day cycle for up to 10 cycles'''
 ===References===
+<!-- This study was presented at the American Society for Clinical Oncology 2011 Annual Meeting, June 3 to 7, Chicago, Illinois, as a poster discussion. -->
-#'''ECOG E2603:''' Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. [https://doi.org/10.1200/jco.2012.42.1529 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23248256 PubMed] NCT00110019
+#'''N0775:''' Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [https://doi.org/10.1002/cncr.27760 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22915053/ PubMed] [https://clinicaltrials.gov/study/NCT00626405 NCT00626405]
-#'''BCH-MM-131101:''' Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. [https://doi.org/10.1200/jco.20.00902 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33444116/ PubMed] NCT02023710
+==Carboplatin & Paclitaxel (CP) {{#subobject:hbq571|Regimen=1}}==
+CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel
-==Carboplatin & Paclitaxel (CP) & Bevacizumab {{#subobject:hjgb71|Regimen=1}}==
+<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen variant #1, 5/175 {{#subobject:6ahg7c|Variant=1}}===
-|[[#top|back to top]]
-|}
-CPB: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:6trg7c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 533: / Line 652: @@
 |[https://doi.org/10.1200/jco.20.00902 Yan et al. 2021 (BCH-MM-131101)]
 |2014-2017
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]
+|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|CP & Bevacizumab]]
-| style="background-color:#91cf60" |Seems to have superior OS <br>Median OS: 14 mo vs 9 mo <br>(HR 0.61, 95% CI 0.41-0.92)
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
 *[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
 '''28-day cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:6a8ye2|Variant=1}}===
-#'''BCH-MM-131101:''' Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. [https://doi.org/10.1200/jco.20.00902 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33444116/ PubMed] NCT02023710
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
-==Carboplatin & nab-Paclitaxel {{#subobject:a013af|Regimen=1}}==
+! style="width: 20%" |Dates of enrollment
-{| class="wikitable" style="float:right; margin-left: 5px;"
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)]
-|}
+|2005-2008
-===Regimen {{#subobject:d78d72|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
-! style="width: 33%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ Kottschade et al. 2011 (N057E1)]
-|2006-2007
-| style="background-color:#91cf61" |Phase II
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] as follows:
-*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, '''given second'''
+**Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, '''given second'''
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
+**Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, '''given second'''
+*[[Paclitaxel (Taxol)]] as follows:
-====Supportive medications====
+**Cycles 1 to 4: 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+**Cycle 5 up to 10: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
+'''21-day cycle for up to 10 cycles'''
+</div></div>
-'''28-day cycle for up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
 ===References===
+#'''ECOG E2603:''' Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. [https://doi.org/10.1200/jco.2012.42.1529 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23248256/ PubMed] [https://clinicaltrials.gov/study/NCT00110019 NCT00110019]
-#'''N057E1:''' Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25659/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21472717 PubMed] NCT00404235
+#'''BCH-MM-131101:''' Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. [https://doi.org/10.1200/jco.20.00902 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33444116/ PubMed] [https://clinicaltrials.gov/study/NCT02023710 NCT02023710]
+==Carboplatin & Paclitaxel (CP) & Bevacizumab {{#subobject:hjgb71|Regimen=1}}==
-==Cisplatin & Dacarbazine {{#subobject:1c1243|Regimen=1}}==
+CPB: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel, '''<u>B</u>'''evacizumab
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:6trg7c|Variant=1}}===
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:fc0483|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2002.20.6.1600 Ridolfi et al. 2002]
+|[https://doi.org/10.1200/jco.20.00902 Yan et al. 2021 (BCH-MM-131101)]
-|1997-1999
+|2014-2017
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-|[[Melanoma_-_historical#Cisplatin.2C_Dacarbazine.2C_IL-2.2C_IFN_alfa-2b_.2B.2F-_Carmustine|Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine]]
+|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 14 vs 9 mo<br>(HR 0.61, 95% CI 0.41-0.92)<br><br>Superior PFS (primary endpoint)<br>Median PFS: 4.8 vs 3 mo<br>(HR 0.46, 95% CI 0.31-0.695)
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
-*[[Dacarbazine (DTIC)]] 800 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
-'''21-day cycle for 6 cycles'''
+'''28-day cycles'''
+</div></div>
 ===References===
+#'''BCH-MM-131101:''' Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. [https://doi.org/10.1200/jco.20.00902 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33444116/ PubMed] [https://clinicaltrials.gov/study/NCT02023710 NCT02023710]
-#Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. [https://doi.org/10.1200/jco.2002.20.6.1600 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11896110 PubMed]
+==Carboplatin & nab-Paclitaxel {{#subobject:a013af|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Cisplatin, Dacarbazine, Paclitaxel {{#subobject:12c753|Regimen=1}}==
+===Regimen {{#subobject:d78d72|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:9b0171|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 ! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
+! style="width: 33%" |Dates of enrollment
 ! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1097/coc.0b013e3181942a1f Papadopoulos et al. 2009]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ Kottschade et al. 2011 (N057E1)]
-|NR in abstract
+|2006-2007
-| style="background-color:#91cf61" |Phase I/II
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Note: cycle length is not specified in the abstract. This is the suggested phase II dosing.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, '''given second'''
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 4
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
-*[[Dacarbazine (DTIC)]] 800 mg/m<sup>2</sup> IV once on day 1
+====Supportive therapy====
-*[[Paclitaxel (Taxol)]] 120 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
+'''28-day cycle for up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
-'''Continued indefinitely'''
+</div></div>
 ===References===
+#'''N057E1:''' Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. [https://doi.org/10.1002/cncr.25659 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21472717/ PubMed] [https://clinicaltrials.gov/study/NCT00404235 NCT00404235]
-#Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. [https://doi.org/10.1097/coc.0b013e3181942a1f link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19506454 PubMed]
+==Cisplatin & Dacarbazine {{#subobject:1c1243|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Dacarbazine monotherapy {{#subobject:d8ug9b|Regimen=1}}==
+===Regimen {{#subobject:fc0483|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.2002.20.6.1600 Ridolfi et al. 2002]
+|1997-1999
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Melanoma_-_historical#Cisplatin.2C_Dacarbazine.2C_IL-2.2C_IFN_alfa-2b_.2B.2F-_Carmustine|Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
+*[[Dacarbazine (DTIC)]] 800 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 6 cycles'''
+</div></div>
+===References===
+#Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. [https://doi.org/10.1200/jco.2002.20.6.1600 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11896110/ PubMed]
+==Cisplatin, Dacarbazine, Paclitaxel {{#subobject:12c753|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:9b0171|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1097/coc.0b013e3181942a1f Papadopoulos et al. 2009]
+|2000-04 to 2002-09
+| style="background-color:#91cf61" |Phase 1/2
 |-
-|[[#top|back to top]]
 |}
-===Example orders===
+''Note: This is the suggested phase 2 dosing.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4
+*[[Dacarbazine (DTIC)]] 800 mg/m<sup>2</sup> IV once on day 1
+*[[Paclitaxel (Taxol)]] 120 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8
+'''21-day cycles (see note)'''
+</div></div>
+===References===
+#Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. [https://doi.org/10.1097/coc.0b013e3181942a1f link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19506454/ PubMed]
-*[[Example orders for Dacarbazine (DTIC) in melanoma]]
+==CVD (Vindesine) {{#subobject:9gt161|Regimen=1}}==
+CVD: '''<u>C</u>'''isplatin, '''<u>V</u>'''indesine, '''<u>D</u>'''acarbazine
-===Regimen variant #1, 850 mg/m<sup>2</sup> q3wk {{#subobject:b6dcb3|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, q3wk {{#subobject:6bgtye|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)]
+|[https://doi.org/10.1093/annonc/mdl007 Bajetta et al. 2006]
-|2006-2008
+|1999-2003
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Dacarbazine_.26_Ipilimumab|Dacarbazine & Ipilimumab]]
+|[[Regimen_classes#Biochemotherapy|Biochemotherapy]]
-| style="background-color:#d73027" |Inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
+*[[Vindesine (Eldisine)]] 2.5 mg/m<sup>2</sup> IV once on day 1
+*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
-'''21-day cycle for 8 cycles'''
+'''21-day cycles'''
+</div></div><br>
-===Regimen variant #2, 850 mg/m<sup>2</sup> q4wk {{#subobject:954862|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q4wk {{#subobject:6b20de|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdj138 Schadendorf et al. 2006]
+|[https://doi.org/10.1016/s0959-8049(98)00068-9 Jungnelius et al. 1998]
-|2000-2003
+|NR
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|Autologous peptide-pulsed monocyte-derived dendritic cells
+|[[Melanoma#Dacarbazine_.26_Vindesine|Dacarbazine & Vindesine]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cisplatin (Platinol)]] as follows:
-*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
+**Cycles 1 to 3: 100 mg/m<sup>2</sup> IV over 30 minutes once on day 1
+*[[Vindesine (Eldisine)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 '''28-day cycles'''
+</div></div>
+===References===
+#Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. [https://doi.org/10.1016/s0959-8049(98)00068-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9849419/ PubMed]
+#Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. [https://doi.org/10.1093/annonc/mdl007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16469753/ PubMed]
-===Regimen variant #3, 1000 mg/m<sup>2</sup> q3wk {{#subobject:beug4c|Variant=1}}===
+==Dacarbazine monotherapy {{#subobject:d8ug9b|Regimen=1}}==
+===Example orders===
+*[[Example orders for Dacarbazine (DTIC) in melanoma]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 850 mg/m<sup>2</sup> q3wk {{#subobject:b6dcb3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2006.06.0483 Bedikian et al. 2006 (AGENDA)]
+|[https://doi.org/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)]
-|2000-2003
+|2006-2008
 | style="background-color:#1a9851" |Phase 3 (C)
-|Dacarbazine & Oblimersen
+|[[#Dacarbazine_.26_Ipilimumab|Dacarbazine & Ipilimumab]]
-| style="background-color:#fee08b" |Might have inferior OS<br>Median OS: 7.8 vs 9 mo<br>(HR 1.15, 95% CI 0.99-1.33)
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)]
-|2013-2014
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Nivolumab_monotherapy_2|Nivolumab]]
 | style="background-color:#d73027" |Inferior OS
 |-
 |}
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
-*[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 8 cycles'''
+</div></div><br>
-'''21-day cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 850 mg/m<sup>2</sup> q4wk {{#subobject:954862|Variant=1}}===
-===References===
-#Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. [https://doi.org/10.1093/annonc/mdj138 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16418308 PubMed]
-#'''AGENDA:''' Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. Epub 2006 Sep 11. [https://doi.org/10.1200/jco.2006.06.0483 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16966688/ PubMed] NCT00518895
-#'''CA184-024:''' Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1104621 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21639810 PubMed] NCT00324155
-##'''Update:''' Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. [https://doi.org/10.1200/jco.2014.56.6018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25713437 PubMed]
-#'''CheckMate 066:''' Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1412082 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25399552 PubMed] NCT01721772
-##'''Update:''' Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25.  [https://jamanetwork.com/journals/jamaoncology/article-abstract/2707224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30422243 PubMed]
-##'''Update:''' Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. [https://doi.org/10.1200/jco.20.00995 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676881/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32997575 PubMed]
-==Dacarbazine & Ipilimumab {{#subobject:5754a8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:7b4884|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)]
+|[https://doi.org/10.1093/annonc/mdj138 Schadendorf et al. 2006]
-|2006-2008
+|2000-2003
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Dacarbazine_monotherapy|Dacarbazine]]
+|Autologous peptide-pulsed monocyte-derived dendritic cells
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
-*[[Dacarbazine (DTIC)]] as follows:
+'''28-day cycles'''
-**Cycles 1 to 8: 850 mg/m<sup>2</sup> IV once on day 1
+</div></div><br>
-====Immunotherapy====
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Ipilimumab (Yervoy)]] as follows:
+===Regimen variant #3, 900 mg/m<sup>2</sup> q3wk {{#subobject:a17084|Variant=1}}===
-**Cycles 1 to 4: 10 mg/kg IV once on day 1
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-**Cycle 9 onwards: 10 mg/kg IV once on day 1
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-'''21-day cycle for 8 cycles, then 12-week cycles'''
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
-===References===
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-#'''CA184-024:''' Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [https://www.nejm.org/doi/full/10.1056/NEJMoa1104621 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21639810 PubMed] NCT00324155
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598549/ Daponte et al. 2013 (SICOG 0109)]
-##'''Update:''' Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. [https://doi.org/10.1200/jco.2014.56.6018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25713437 PubMed]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (C)
-==Ipilimumab monotherapy {{#subobject:cbz3f4|Regimen=1}}==
+|1. [[#Dacarbazine_.26_Fotemustine_999|Dacarbazine & Fotemustine]]<br>2. [[#Dacarbazine_.26_Interferon_alfa-2b_999|Dacarbazine & IFN alfa-2b]]<br> 3. [[#Dacarbazine.2C_Fotemustine.2C_Interferon_alfa-2b_999|Dacarbazine, Fotemustine, IFN alfa-2b]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[[#top|back to top]]
-|}
-===Example orders===
-*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
-===Regimen {{#subobject:33ug6a|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
 |-
 |}
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Dacarbazine (DTIC)]] 900 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 1000 mg/m<sup>2</sup> q3wk {{#subobject:beug4c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 17%" |Study
+! style="width: 20%" |Study
-! style="width: 15%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
+! style="width: 20%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)]
+|[https://doi.org/10.1200/jco.1999.17.9.2745 Chapman et al. 1999]
-| rowspan="2" |2013-2014
+|1991-1997
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
+|[[#Dartmouth_regimen_333|Dartmouth regimen]]
-| style="background-color:#d73027" |Inferior OS<sup>1</sup>
+| style="background-color:#fee08b" |Might have inferior ORR
-| style="background-color:#eeee01" |Equivalent HRQoL
 |-
-|2. [[#Nivolumab_monotherapy_2|Nivolumab]]
+|[https://doi.org/10.1200/jco.2006.06.0483 Bedikian et al. 2006 (AGENDA)]
-| style="background-color:#d73027" |Inferior OS<sup>1</sup>
+|2000-2003
-| style="background-color:#eeee01" |Equivalent HRQoL
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Dacarbazine_.26_Oblimersen_777|Dacarbazine & Oblimersen]]
+| style="background-color:#fee08b" |Might have inferior OS<br>Median OS: 7.8 vs 9 mo<br>(HR 1.15, 95% CI 0.99-1.33)
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1414428 Postow et al. 2015 (CheckMate 069)]
+|[https://doi.org/10.1200/JCO.2007.11.9941 Testori et al. 2008 (C-100-21)]
-|2013-2014
+|2002-2004
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
+|[[#Vitespen_monotherapy_999|Vitespen]]
-| style="background-color:#d73027" |Inferior PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-| style="background-color:#d3d3d3" |
 |-
-|}
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303777/ Bedikian et al. 2010]
-''<sup>1</sup>Reported efficacy for CheckMate 067 is based on the 2019 update.''
+|2002-2007
-====Immunotherapy====
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#DHA-paclitaxel_monotherapy_999|DHA-paclitaxel]]
-*[[Ipilimumab (Yervoy)]] 3 mg/kg IV over 90 minutes once on day 1
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-'''21-day cycle for 4 cycles'''
-===References===
-#'''CheckMate 069:''' Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414428 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25891304 PubMed] NCT01927419
-##'''Update:''' Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30366-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27622997 PubMed]
-#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1504030 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26027431 PubMed] NCT01844505
-##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28651159 PubMed]
-##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30700-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170 PubMed]
-##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://www.nejm.org/doi/full/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797 PubMed]
-==Ipilimumab & Nivolumab {{#subobject:51gu10|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ Ribas et al. 2013 (A3671009)]
-|}
+|2006-03 to 2007-07
-===Regimen variant #1 {{#subobject:3a481c|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+|[[#Tremelimumab_monotherapy_999|Tremelimumab]]
-! style="width: 17%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-! style="width: 15%" |Years of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652683/ Ugurel et al. 2017 (ChemoSensMM)]
-| rowspan="2" |2013-2014
+|2008-2012
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Ipilimumab_monotherapy_2|Ipilimumab]]
+|Chemosensitivity-directed therapy:<br>1. [[#Cisplatin_.26_Paclitaxel_999|Cisplatin & Paclitaxel]]<br>2. [[#Cytarabine_.26_Treosulfan_999|Cytarabine & Treosulfan]]<br>3. [[#Gemcitabine_.26_Treosulfan|Gemcitabine & Treosulfan]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup>
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-| style="background-color:#eeee01" |Equivalent HRQoL
 |-
-|2. [[#Nivolumab_monotherapy_2|Nivolumab]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ Hersh et al. 2015 (CA033)]
-| style="background-color:#1a9850" |Superior PFS
+|2009-04 to 2011-06
-| style="background-color:#eeee01" |Equivalent HRQoL
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
+| style="background-color:#fc8d59" |Seems to have inferior PFS
+|-
+|[https://doi.org/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)]
+|2013-01 to 2014-02
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Nivolumab_monotherapy_2|Nivolumab]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
+<div class="toccolours" style="background-color:#b3e2cd">
-''Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
+====Chemotherapy====
-====Immunotherapy====
+*[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycles'''
-*[[Ipilimumab (Yervoy)]] as follows:
+</div></div><br>
-**Cycles 1 to 4: 3 mg/kg IV once on day 1
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Nivolumab (Opdivo)]] as follows:
+===Regimen variant #5, 1000 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:3f3475|Variant=1}}===
-**Cycles 1 to 4: 1 mg/kg IV once on day 1
-**Cycle 5 onwards: 3 mg/kg IV once on day 1
-'''21-day cycle for 4 cycles, then 14-day cycles'''
-===Regimen variant #2, "NIVO1+IPI3", weight-based maintenance {{#subobject:fa88a8|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1414428 Postow et al. 2015 (CheckMate 069)]
+|[https://doi.org/10.1200/jco.1998.16.5.1743 Falkson et al. 2003 (ECOG E3690)]
-|2013-2014
+|NR
-| style="background-color:#1a9851" |Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ipilimumab_monotherapy_2|Ipilimumab]]
+|1. [[#Dacarbazine_.26_Interferon_alfa-2b_888|DTIC & Interferon]]<br>2. [[Melanoma_-_historical#Dacarbazine_.26_Tamoxifen|DTIC & Tamoxifen]]<br> 3. [[#Dacarbazine.2C_Interferon_alfa-2b.2C_Tamoxifen_888|DTIC, Interferon, Tamoxifen]]
-| style="background-color:#1a9850" |Superior PFS
+| style="background-color:#fc8d59" |Seems to have inferior ORR
+|-
 |}
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Ipilimumab (Yervoy)]] as follows:
+*[[Dacarbazine (DTIC)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
-**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given second'''
+'''28-day cycles'''
-*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, '''given first'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''21-day cycle for 4 cycles, then 14-day cycles'''
+===Regimen variant #6, 1250 mg/m<sup>2</sup>, split doses, q3wk {{#subobject:4bacb3|Variant=1}}===
-===Regimen variant #3, "NIVO1+IPI3", flat-dose maintenance {{#subobject:3ab34c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 17%" |Study
+! style="width: 20%" |Study
-! style="width: 15%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
+! style="width: 20%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ Lebbé et al. 2019 (CheckMate 511)]
+|[https://doi.org/10.1200/jco.2000.18.1.158 Middleton et al. 2000b]
-|2016-2017
+|1995-1997
-| style="background-color:#1a9851" |Phase 3b/IV (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]; NIVO3+IPI1
+|[[#Temozolomide_monotherapy|Temozolomide]]
-| style="background-color:#d3d3d3" |Not evaluated
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-| style="background-color:#d73027" |More grade 3 to 5 TRAEs
 |-
 |}
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Ipilimumab (Yervoy)]] as follows:
+*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
-**Cycles 1 to 4: 3 mg/kg IV once on day 1
+'''21-day cycles'''
-*[[Nivolumab (Opdivo)]] as follows:
+</div></div><br>
-**Cycles 1 to 4: 1 mg/kg IV once on day 1
+<div class="toccolours" style="background-color:#eeeeee">
-**Cycle 5 onwards: 480 mg IV once on day 1
+===Regimen variant #7, 1250 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:f3110c|Variant=1}}===
-'''21-day cycle for 4 cycles, then 28-day cycles'''
-===Regimen variant #4, "NIVO3+IPI1", flat-dose maintenance {{#subobject:3a48jc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 17%" |Study
+! style="width: 20%" |Study
-! style="width: 15%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
+! style="width: 20%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ Lebbé et al. 2019 (CheckMate 511)]
+|[https://doi.org/10.1200/JCO.2004.04.165 Avril et al. 2004]
-|2016-2017
+|1998-2000
-| style="background-color:#1a9851" |Phase 3b/IV (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]; NIVO1+IPI3
+|[[#Fotemustine_monotherapy|Fotemustine]]
-| style="background-color:#d3d3d3" |Not evaluated
+| style="background-color:#fc8d59" |Seems to have inferior ORR
-| style="background-color:#1a9850" |Fewer grade 3 to 5 TRAEs
 |-
 |}
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Ipilimumab (Yervoy)]] as follows:
+*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
-**Cycles 1 to 4: 1 mg/kg IV once on day 1
+'''28-day cycles'''
-*[[Nivolumab (Opdivo)]] as follows:
+</div></div>
-**Cycles 1 to 4: 3 mg/kg IV once on day 1
-**Cycle 5 onwards: 480 mg IV once on day 1
-'''21-day cycle for 4 cycles, then 28-day cycles'''
 ===References===
+#'''ECOG E3690:''' Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; [[Study_Groups#ECOG|ECOG]]. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. [https://doi.org/10.1200/jco.1998.16.5.1743 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9586887/ PubMed]
+#Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. [https://doi.org/10.1200/jco.1999.17.9.2745 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561349/ PubMed]
+#Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [https://doi.org/10.1200/jco.2000.18.1.158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10623706/ PubMed]
+#Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. [https://doi.org/10.1200/JCO.2004.04.165 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15020614/ PubMed]
+#Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. [https://doi.org/10.1093/annonc/mdj138 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16418308/ PubMed]
+#'''AGENDA:''' Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. Epub 2006 Sep 11. [https://doi.org/10.1200/jco.2006.06.0483 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16966688/ PubMed] [https://clinicaltrials.gov/study/NCT00518895 NCT00518895]
+#'''C-100-21:''' Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. [https://doi.org/10.1200/JCO.2007.11.9941 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/18281670/ PubMed]
+#Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. [https://doi.org/10.1093/annonc/mdq438 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303777/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20855467/ PubMed]
+#'''CA184-024:''' Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [https://doi.org/10.1056/NEJMoa1104621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21639810/ PubMed] [https://clinicaltrials.gov/study/NCT00324155 NCT00324155]
+##'''Update:''' Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. [https://doi.org/10.1200/jco.2014.56.6018 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5795709/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25713437/ PubMed]
+<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and 25th Annual Meeting of the International Society for Biological Therapy of Cancer, Washington, DC, October 2-4, 2010. -->
+#'''A3671009:''' Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. [https://doi.org/10.1200/JCO.2012.44.6112 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23295794/ PubMed] [https://clinicaltrials.gov/study/NCT00257205 NCT00257205]
+#'''SICOG 0109:''' Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-38 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598549/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23402397/ PubMed] [https://clinicaltrials.gov/study/NCT01359956 NCT01359956]
+#'''CheckMate 066:''' Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [https://doi.org/10.1056/NEJMoa1412082 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25399552/ PubMed] [https://clinicaltrials.gov/study/NCT01721772 NCT01721772]
+##'''Update:''' Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25.  [https://jamanetwork.com/journals/jamaoncology/article-abstract/2707224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30422243/ PubMed]
+##'''Update:''' Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. [https://doi.org/10.1200/jco.20.00995 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676881/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32997575/ PubMed]
+#'''CA033:''' Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. [https://doi.org/10.1093/annonc/mdv324 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26410620/ PubMed] [https://clinicaltrials.gov/study/NCT00864253 NCT00864253]
+#'''ChemoSensMM:''' Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. [https://doi.org/10.18632/oncotarget.18635 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652683/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29100289/ PubMed] [https://clinicaltrials.gov/study/NCT00779714 NCT00779714]
-#'''CheckMate 069:''' Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414428 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25891304 PubMed] NCT01927419
+==Dacarbazine & Ipilimumab {{#subobject:5754a8|Regimen=1}}==
-##'''Update:''' Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30366-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27622997 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1504030 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26027431 PubMed] NCT01844505
+===Regimen {{#subobject:7b4884|Variant=1}}===
-##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28651159 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30700-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170 PubMed]
+! style="width: 20%" |Study
-##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://www.nejm.org/doi/full/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797 PubMed]
+! style="width: 20%" |Dates of enrollment
-#'''CheckMate 511:''' Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. Epub 2019 Feb 27. [https://doi.org/10.1200/jco.18.01998 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30811280/ PubMed] NCT02714218
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
-==Nivolumab monotherapy {{#subobject:6aoobd|Regimen=1}}==
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)]
-|}
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-===Regimen variant #1, weight-based {{#subobject:2gze51|Variant=1}}===
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-90-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 17%" |Study
-! style="width: 15%" |Years of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)]
+|} -->
-|2013-2014
+|2006-2008
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#Dacarbazine_monotherapy|Dacarbazine]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>5-year OS: 39% vs 17% <br>(HR 0.50, 95% CI 0.40-0.63)
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 11.2 vs 9.1 mo<br>(HR 0.69, 95% CI 0.57-0.84)
-|
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)]
-| rowspan="2" |2013-2014
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|1. [[#Ipilimumab_monotherapy_2|Ipilimumab]]
-| style="background-color:#1a9850" |Superior OS<sup>2</sup> <br>Median OS: 37 mo vs 20 mo <br>(HR 0.63)
-| style="background-color:#eeee01" |Equivalent HRQoL
-|-
-|2. [[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
-| style="background-color:#d73027" |Inferior PFS
-| style="background-color:#eeee01" |Equivalent HRQoL
 |-
 |}
-''<sup>1</sup>Reported efficacy for CheckMate 066 is based on the 2020 update.''<br>
+''<sup>1</sup>Reported efficacy is based on the 2015 update.''
-''<sup>2</sup>Reported efficacy for CheckMate 067 is based on the 2019 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Dacarbazine (DTIC)]] as follows:
+**Cycles 1 to 8: 850 mg/m<sup>2</sup> IV once on day 1
 ====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] as follows:
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+**Cycles 1 to 4: 10 mg/kg IV once on day 1
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
+**Cycle 9 onwards: 10 mg/kg IV once on day 1
+'''21-day cycle for 8 cycles, then 12-week cycles'''
-'''14-day cycles'''
+</div></div>
+===References===
-===Regimen variant #2, flat dosing {{#subobject:2gze52|Variant=1}}===
+#'''CA184-024:''' Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [https://doi.org/10.1056/NEJMoa1104621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21639810/ PubMed] [https://clinicaltrials.gov/study/NCT00324155 NCT00324155]
+##'''Update:''' Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. [https://doi.org/10.1200/jco.2014.56.6018 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5795709/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25713437/ PubMed]
+==Dacarbazine & Vindesine {{#subobject:97ve61|Regimen=1}}==
+DV: '''<u>D</u>'''acarbazine & '''<u>V</u>'''indesine
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:6b20de|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 20%" |Study
-!style="width: 20%"|Years of enrollment
+! style="width: 20%" |Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 20%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/nejmoa2109970 Tawbi et al. 2022 (RELATIVITY-047)]
+|[https://doi.org/10.1016/s0959-8049(98)00068-9 Jungnelius et al. 1998]
-|2018-2020
+|NR
-| style="background-color:#1a9851" |Phase 2/3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Nivolumab & Relatlimab
+|[[Melanoma_-_historical#CVD_.28Vindesine.29|CVD]]
-| style="background-color:#d73027" |Inferior PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
+*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
+*[[Vindesine (Eldisine)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 '''28-day cycles'''
+</div></div>
 ===References===
+#Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. [https://doi.org/10.1016/s0959-8049(98)00068-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9849419/ PubMed]
-#'''CheckMate 066:''' Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1412082 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25399552 PubMed] NCT01721772
+==Fotemustine monotherapy {{#subobject:92d0c6|Regimen=1}}==
-##'''Update:''' Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25.  [https://jamanetwork.com/journals/jamaoncology/article-abstract/2707224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30422243 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-##'''Update:''' Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. [https://doi.org/10.1200/jco.20.00995 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676881/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32997575 PubMed]
+===Regimen {{#subobject:ff4f50|Variant=1}}===
-#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1504030 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26027431 PubMed] NCT01844505
-##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28651159 PubMed]
-##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30700-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170 PubMed]
-##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://www.nejm.org/doi/full/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797 PubMed]
-#'''RELATIVITY-047:''' Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. [https://doi.org/10.1056/nejmoa2109970 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34986285/ PubMed] NCT03470922
-#'''PIVOT IO 001:''' NCT03635983
-==Pembrolizumab monotherapy {{#subobject:78ub8c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:25acnp|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/j.annonc.2020.12.004 Gogas et al. 2020 (IMspire170)]
+|[https://doi.org/10.1200/JCO.2004.04.165 Avril et al. 2004]
-|2017-2019
+|1998-2000
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|Cobimetinib & Atezolizumab
+|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#91cf60" |Seems to have superior ORR (primary endpoint)
 |-
 |}
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+*[[Fotemustine (Muphoran)]] as follows:
+**Cycle 1: 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-'''21-day cycles'''
+**Cycle 2 onwards: 100 mg/m<sup>2</sup> IV once on day 1
+'''8-week course, then 21-day cycles'''
+</div></div>
 ===References===
+#Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. [https://doi.org/10.1200/JCO.2004.04.165 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15020614/ PubMed]
-#'''IMspire170:''' Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Francesco Ferrucci P, Pigozzo J, Rutkowski P, Mackiewicz J, Rooney I, Voulgari A, Troutman S, Pitcher B, Guo Y, Yan Y, Castro M, Mulla S, Flaherty K, Arance A. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021 Mar;32(3):384-394. Epub 2020 Dec 10. [https://doi.org/10.1016/j.annonc.2020.12.004 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33309774/ PubMed] NCT03273153
+==Ipilimumab monotherapy {{#subobject:cbz3f4|Regimen=1}}==
-#'''KEYNOTE-034:''' NCT02263508
+===Example orders===
+*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
-== Relatlimab & Nivolumab {{#subobject:6aoobd|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:33ug6a|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:25acnp|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 17%" |Study
-!style="width: 20%"|Years of enrollment
+! style="width: 15%" |Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+! style="width: 17%" |Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[https://doi.org/10.1056/nejmoa2109970 Tawbi et al. 2022 (RELATIVITY-047)]
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ Larkin et al. 2015 (CheckMate 067)]
-|2018-2020
+| rowspan="2" |2013-07 to 2014-03
-| style="background-color:#1a9851" |Phase 2/3 (C)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|Nivolumab
+|1. [[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
-| style="background-color:#1a9851" |Superior PFS
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
+| style="background-color:#eeee01" |Equivalent HRQoL
 |-
-|}
+|2. [[#Nivolumab_monotherapy_2|Nivolumab]]
-====Immunotherapy====
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-*Relatlimab 160 mg IV once on day 1
+| style="background-color:#eeee01" |Equivalent HRQoL
-*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ Postow et al. 2015 (CheckMate 069)]
-'''28-day cycles'''
+|2013-09-16 to 2014-02-06
+| style="background-color:#1a9851" |Phase 3 (C)
-===References===
+|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
+| style="background-color:#d73027" |Inferior PFS
-#'''RELATIVITY-047:''' Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. [https://doi.org/10.1056/nejmoa2109970 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34986285/ PubMed] NCT03470922
+| style="background-color:#d3d3d3" |
-==Temozolomide & Bevacizumab {{#subobject:511376|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-TB: '''<u>T</u>'''emozolomide & '''<u>B</u>'''evacizumab
+''<sup>1</sup>Reported efficacy for CheckMate 067 is based on the 2021 update.''
-===Regimen {{#subobject:42ead6|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] 3 mg/kg IV over 90 minutes once on day 1
+'''21-day cycle for 4 cycles'''
+</div></div>
+===References===
+#'''CheckMate 069:''' Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [https://doi.org/10.1056/NEJMoa1414428 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25891304/ PubMed] [https://clinicaltrials.gov/study/NCT01927419 NCT01927419]
+##'''Update:''' Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. [https://doi.org/10.1016/S1470-2045(16)30366-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5630525/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27622997/ PubMed]
+#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://doi.org/10.1056/NEJMoa1504030 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26027431/ PubMed] [https://clinicaltrials.gov/study/NCT01844505 NCT01844505]
+##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://doi.org/10.1016/j.ejca.2017.05.031 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5737813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651159/ PubMed]
+##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. [https://doi.org/10.1056/nejmoa1709684 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5706778/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28889792/ PubMed]
+##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30700-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170/ PubMed]
+##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://doi.org/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797/ PubMed]
+##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. [https://doi.org/10.1200/jco.21.02229 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34818112/ PubMed]
+==Ipilimumab & Nivolumab {{#subobject:51gu10|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:3a481c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+! style="width: 17%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 15%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+! style="width: 17%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)]
+|-
-|2008-2010
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ Larkin et al. 2015 (CheckMate 067)]
-| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|[[#ABC|ABC]]
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-77-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-| style="background-color:#fc8d59" |Seems to have inferior PFS6
+|-
+|} -->
+| rowspan="2" |2013-07 to 2014-03
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|1. [[#Ipilimumab_monotherapy_2|Ipilimumab]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 72.1 vs 19.9 mo<br>(HR 0.42, 95% CI 0.35-0.51)
+| style="background-color:#eeee01" |Equivalent HRQoL
+|-
+|2. [[#Nivolumab_monotherapy_2|Nivolumab]]
+| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 11.5 vs 6.9 mo<br>(HR 0.79, 95% CI 0.65-0.97)
+| style="background-color:#eeee01" |Equivalent HRQoL
 |-
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
+''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
-*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-====Targeted therapy====
+*[[Ipilimumab (Yervoy)]] as follows:
+**Cycles 1 to 4: 3 mg/kg IV once on day 1
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
+*[[Nivolumab (Opdivo)]] as follows:
+**Cycles 1 to 4: 1 mg/kg IV once on day 1
-'''28-day cycles'''
+**Cycle 5 onwards: 3 mg/kg IV once on day 1
+'''21-day cycle for 4 cycles, then 14-day cycles'''
-===References===
+</div></div><br>
-<!-- This study was presented at the American Society for Clinical Oncology 2011 Annual Meeting, June 3 to 7, Chicago, Illinois, as a poster discussion. -->
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, "NIVO1+IPI3", weight-based maintenance {{#subobject:fa88a8|Variant=1}}===
-#'''N0775:''' Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.27760/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22915053 PubMed] NCT00626405
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
-=Metastatic or unresectable disease, second-line=
+! style="width: 20%" |Dates of enrollment
-==Carboplatin & Paclitaxel (CP) {{#subobject:610571|Regimen=1}}==
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ Postow et al. 2015 (CheckMate 069)]
-|}
+|2013-09-16 to 2014-02-06
-CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin
+|[[#Ipilimumab_monotherapy_2|Ipilimumab]]
-===Regimen variant #1, AUC 2/100 {{#subobject:5edf1c|Variant=1}}===
+| style="background-color:#1a9850" |Superior PFS (secondary endpoint)<br>Median PFS: NYR vs 4.4 mo<br>(HR 0.40, 95% CI 0.23-0.68)<br><br>Superior ORR (primary endpoint)
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.21611/full Rao et al. 2006]
-| style="background-color:#ffffbe" |Retrospective
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] as follows:
+**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given second'''
+*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, '''given first'''
+'''21-day cycle for 4 cycles, then 14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15
+===Regimen variant #3, "NIVO1+IPI3", flat-dose maintenance {{#subobject:3ab34c|Variant=1}}===
-*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-'''28-day cycles'''
-===Regimen variant #2, AUC 6/175 {{#subobject:06b48b|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+! style="width: 17%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 15%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+! style="width: 17%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ Lebbé et al. 2019 (CheckMate 511)]
-|2012-2014
+|2016-04-04 to 2017-03-27
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3b/4 (C)
-|[[#Nivolumab_monotherapy_3|Nivolumab]]
+|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]; NIVO3+IPI1
-| style="background-color:#d73027" |Inferior ORR
+| style="background-color:#d3d3d3" |Not evaluated
+| style="background-color:#d73027" |More grade 3 to 5 TRAEs
 |-
 |}
-''Note: this study did not meet the co-primary endpoint of OS.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] as follows:
-*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
+**Cycles 1 to 4: 3 mg/kg IV once on day 1
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
+*[[Nivolumab (Opdivo)]] as follows:
+**Cycles 1 to 4: 1 mg/kg IV once on day 1
-'''21-day cycles'''
+**Cycle 5 onwards: 480 mg IV once on day 1
+'''21-day cycle for 4 cycles, then 28-day cycles'''
-===Regimen variant #3, AUC 6/225 x 4, then AUC 5/175 {{#subobject:6a83f2|Variant=1}}===
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, "NIVO3+IPI1", flat-dose maintenance {{#subobject:3a48jc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+! style="width: 17%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 15%" |Dates of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+! style="width: 17%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|[https://doi.org/10.1200/jco.2007.15.7636 Hauschild et al. 2009 (Bayer 11718)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ Lebbé et al. 2019 (CheckMate 511)]
-|2005-2006
+|2016-04-04 to 2017-03-27
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3b/4 (E-switch-ic)
-|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
+|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]; NIVO1+IPI3
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#d3d3d3" |Not evaluated
-|-
+| style="background-color:#1a9850" |Fewer grade 3 to 5 TRAEs
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)]
-|2005-2008
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-*[[Carboplatin (Paraplatin)]] as follows:
+*[[Ipilimumab (Yervoy)]] as follows:
-**Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, '''given second'''
+**Cycles 1 to 4: 1 mg/kg IV once on day 1
-**Cycle 5 onwards: AUC 5 IV over 30 minutes once on day 1, '''given second'''
+*[[Nivolumab (Opdivo)]] as follows:
-*[[Paclitaxel (Taxol)]] as follows:
+**Cycles 1 to 4: 3 mg/kg IV once on day 1
-**Cycles 1 to 4: 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+**Cycle 5 onwards: 480 mg IV once on day 1
-**Cycle 5 onwards: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+'''21-day cycle for 4 cycles, then 28-day cycles'''
+</div></div>
-'''21-day cycle for up to 10 cycles'''
+===References===
+#'''CheckMate 069:''' Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [https://doi.org/10.1056/NEJMoa1414428 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25891304/ PubMed] [https://clinicaltrials.gov/study/NCT01927419 NCT01927419]
-===Regimen variant #4, 200/100, 6 out of 8 weeks {{#subobject:64b1c2|Variant=1}}===
+##'''Update:''' Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. [https://doi.org/10.1016/S1470-2045(16)30366-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5630525/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27622997/ PubMed]
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://doi.org/10.1056/NEJMoa1504030 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26027431/ PubMed] [https://clinicaltrials.gov/study/NCT01844505 NCT01844505]
-! style="width: 20%" |Study
+##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://doi.org/10.1016/j.ejca.2017.05.031 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5737813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651159/ PubMed]
-! style="width: 20%" |Years of enrollment
+##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. [https://doi.org/10.1056/nejmoa1709684 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5706778/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28889792/ PubMed]
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30700-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170/ PubMed]
-! style="width: 20%" |Comparator
+##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://doi.org/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797/ PubMed]
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24.[https://doi.org/10.1200/jco.21.02229 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34818112/ PubMed]
+#'''CheckMate 511:''' Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. Epub 2019 Feb 27. [https://doi.org/10.1200/jco.18.01998 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30811280/ PubMed] [https://clinicaltrials.gov/study/NCT02714218 NCT02714218]
+==Nivolumab monotherapy {{#subobject:6aoobd|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, q2wk {{#subobject:2gze51|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
+! style="width: 15%" |Dates of enrollment
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://doi.org/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-89-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
+|2013-01 to 2014-02
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|[[#Dacarbazine_monotherapy|Dacarbazine]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>OS60: 39% vs 17%<br>(HR 0.50, 95% CI 0.40-0.63)
+|
+|-
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ Larkin et al. 2015 (CheckMate 067)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-77-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
+| rowspan="2" |2013-07 to 2014-03
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#Ipilimumab_monotherapy_2|Ipilimumab]]
+| style="background-color:#1a9850" |Superior OS<sup>2</sup> (co-primary endpoint)<br>Median OS: 36.9 vs 19.9 mo<br>(HR 0.53, 95% CI 0.44-0.64)
+| style="background-color:#eeee01" |Equivalent HRQoL
 |-
-|[https://journals.lww.com/melanomaresearch/Citation/2003/10000/Randomized_phase_II_study_of_weekly_paclitaxel.12.aspx Zimpfer-Rechner et al. 2003]
+|2. [[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
-|1998-2000
+| style="background-color:#d73027" |Inferior PFS (co-primary endpoint)
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+| style="background-color:#eeee01" |Equivalent HRQoL
-|[[#Paclitaxel_monotherapy|Paclitaxel]]
-| style="background-color:#ffffbf" |Did not meet primary efficacy endpoints
 |-
 |}
-''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''
+''<sup>1</sup>Reported efficacy for CheckMate 066 is based on the 2020 update.''<br>
-====Chemotherapy====
+''<sup>2</sup>Reported efficacy for CheckMate 067 is based on the 2021 update.''<br>
+''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
-*[[Carboplatin (Paraplatin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-'''8-week cycles'''
+'''14-day cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, q3wk {{#subobject:7gce52|Variant=1}}===
-#Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. [https://journals.lww.com/melanomaresearch/Citation/2003/10000/Randomized_phase_II_study_of_weekly_paclitaxel.12.aspx link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14512795 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''Retrospective:''' Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.21611 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16342250 PubMed]
+!style="width: 20%"|Study
-<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. -->
+!style="width: 20%"|Dates of enrollment
-#'''Bayer 11718:''' Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. [https://doi.org/10.1200/jco.2007.15.7636 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19349552 PubMed] NCT00111007
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25795410 PubMed] NCT01721746
+!style="width: 20%"|Comparator
-##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28671856 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-==Carboplatin & nab-Paclitaxel {{#subobject:a013af|Regimen=1}}==
+|[https://doi.org/10.1200/jco.23.00172 Diab et al. 2023 (PIVOT IO 001)]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+|2018-10-10 to 2021-12-17
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Bempegaldesleukin_monotherapy_999|Bempegaldesleukin]]
+| style="background-color:#91cf60" |Seems to have superior ORR (co-primary endpoint)<br><br>Did not meet co-primary endpoint of PFS
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:d78d72|Variant=1}}===
+''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+<div class="toccolours" style="background-color:#b3e2cd">
-! style="width: 33%" |Study
+====Immunotherapy====
-! style="width: 33%" |Years of enrollment
+*[[Nivolumab (Opdivo)]] 360 mg IV once on day 1
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, q4wk {{#subobject:2gze52|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ Kottschade et al. 2011 (N057E1)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ Tawbi et al. 2022 (RELATIVITY-047)]
-|2006-2007
+|2018-2020
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#1a9851" |Phase 2/3 (C)
+|[[#Nivolumab_.26_Relatlimab|Nivolumab & Relatlimab]]
+| style="background-color:#d73027" |Inferior PFS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, '''given second'''
+*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
+'''28-day cycles'''
+</div></div>
-====Supportive medications====
-*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
-'''28-day cycle for up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
 ===References===
+#'''CheckMate 066:''' Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [https://doi.org/10.1056/NEJMoa1412082 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25399552/ PubMed] [https://clinicaltrials.gov/study/NCT01721772 NCT01721772]
+##'''Update:''' Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25.  [https://jamanetwork.com/journals/jamaoncology/article-abstract/2707224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30422243/ PubMed]
+##'''Update:''' Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. [https://doi.org/10.1200/jco.20.00995 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676881/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32997575/ PubMed]
+#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://doi.org/10.1056/NEJMoa1504030 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26027431/ PubMed] [https://clinicaltrials.gov/study/NCT01844505 NCT01844505]
+##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://doi.org/10.1016/j.ejca.2017.05.031 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5737813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651159/ PubMed]
+##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. [https://doi.org/10.1056/nejmoa1709684 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5706778/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28889792/ PubMed]
+##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30700-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170/ PubMed]
+##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://doi.org/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797/ PubMed]
+##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. [https://doi.org/10.1200/jco.21.02229 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34818112/ PubMed]
+#'''RELATIVITY-047:''' Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. [https://doi.org/10.1056/nejmoa2109970 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34986285/ PubMed] [https://clinicaltrials.gov/study/NCT03470922 NCT03470922]
+##'''Update:''' Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. [https://pubmed.ncbi.nlm.nih.gov/38320023/ PubMed] [https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200239 link to original article]
+#'''PIVOT IO 001:''' Diab A, Gogas H, Sandhu S, Long GV, Ascierto PA, Larkin J, Sznol M, Franke F, Ciuleanu TE, Pereira C, Muñoz Couselo E, Bronzon Damian F, Schenker M, Perfetti A, Lebbe C, Quéreux G, Meier F, Curti BD, Rojas C, Arriaga Y, Yang H, Zhou M, Ravimohan S, Statkevich P, Tagliaferri MA, Khushalani NI. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results. J Clin Oncol. 2023 Oct 20;41(30):4756-4767. Epub 2023 Aug 31. [https://doi.org/10.1200/jco.23.00172 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37651676/ PubMed] [https://clinicaltrials.gov/study/NCT03635983 NCT03635983]
-#'''N057E1:''' Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25659/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21472717 PubMed] NCT00404235
+==Nivolumab & Relatlimab {{#subobject:6abj1d|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==TILs {{#subobject:f33e1b|Regimen=1}}==
+===Regimen {{#subobject:2gzt44|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
-|[[#top|back to top]]
 |}
-TILs: '''<u>T</u>'''umor '''<u>I</u>'''filtrating '''<u>L</u>'''ymphocyte'''<u>s</u>'''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Regimen {{#subobject:12350b|Variant=1}}===
+!style="width: 20%"|Study
-{| class="wikitable" style="width: 40%; text-align:center;"
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Study
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ Tawbi et al. 2022 (RELATIVITY-047)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-330-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 |-
-|[https://pubmed.ncbi.nlm.nih.gov/33979178/ Sarnaik et al. 2021]
+|} -->
-| style="background-color:#91cf61" |Phase II
+|2018-2020
+| style="background-color:#1a9851" |Phase 2/3 (E-RT-esc)
+|[[#Nivolumab_monotherapy_2|Nivolumab]]
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 10.2 vs 4.6 mo<br>(HR 0.78, 95% CI 0.64-0.94)<br><br>Might have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs 34.1 mo<br>(HR 0.80, 95% CI 0.64-1.01)
 |-
 |}
-====Preceding treatment====
+''<sup>1</sup>Reported efficacy is based on the 2023 update.''
-*[[Autologous_HSCT#FC|FC]] lymphodepletion
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Autologous TILs]] administered 24 hours from last dose of fludarabine
+*[[Nivolumab and relatlimab (Opdualag)]] 480/160 mg IV once on day 1
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8-12 hours as tolerated for up to 6 doses starting 3-24 hours after completing lifileucel infusion
+'''28-day cycles'''
+</div></div>
 ===References===
-# Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. doi: 10.1200/JCO.21.00612. Epub 2021 May 12. Erratum in: J Clin Oncol. 2021 Sep 10;39(26):2972. [https://ascopubs.org/doi/full/10.1200/JCO.21.00612 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33979178/ PubMed] NCT02360579
+#'''RELATIVITY-047:''' Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. [https://doi.org/10.1056/nejmoa2109970 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34986285/ PubMed] [https://clinicaltrials.gov/study/NCT03470922 NCT03470922]
+##'''Update:''' Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. [https://pubmed.ncbi.nlm.nih.gov/38320023/ PubMed] [https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200239 link to original article]
-=Metastatic or unresectable disease=
+==Pembrolizumab monotherapy {{#subobject:78ub8c|Regimen=1}}==
-''Note: these regimens have not yet been classified by line of treatment.''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:25acnp|Variant=1}}===
-==CVD (Vindesine) {{#subobject:97b161|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CVD: '''<u>C</u>'''isplatin, '''<u>V</u>'''indesine, '''<u>D</u>'''acarbazine
-===Regimen {{#subobject:6b20de|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ejcancer.com/article/S0959-8049(98)00068-9/fulltext Jungnelius et al. 1998]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870217/ Chesney et al. 2022 (MASTERKEY-265)]
-|NR
+|2016-2018
-| style="background-color:#1a9851" |Phase 3 (E-esc)
-|Dacarbazine & Vindesine
-| style="background-color:#1a9850" |Superior TTP
-|-
-|[https://doi.org/10.1093/annonc/mdl007 Bajetta et al. 2006]
-|1999-2003
 | style="background-color:#1a9851" |Phase 3 (C)
-|Biochemotherapy
+|[[#T-VEC_.26_Pembrolizumab_333|T-VEC & Pembrolizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#fee08b" |Might have inferior PFS<br>Median PFS: 8.5 vs 14.3 mo<br>(HR 1.16, 95% CI 0.96-1.41)
+|-
+|[https://doi.org/10.1016/j.annonc.2020.12.004 Gogas et al. 2020 (IMspire170)]
+|2017-2019
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cobimetinib_.26_Atezolizumab_999|Cobimetinib & Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 5.7 vs 5.5 mo<br>(HR 0.87, 95% CI 0.67-1.14)
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-*[[Vindesine (Eldisine)]] 2.5 mg/m<sup>2</sup> IV once on day 1
-*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
 '''21-day cycles'''
+</div></div>
 ===References===
+#'''IMspire170:''' Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Francesco Ferrucci P, Pigozzo J, Rutkowski P, Mackiewicz J, Rooney I, Voulgari A, Troutman S, Pitcher B, Guo Y, Yan Y, Castro M, Mulla S, Flaherty K, Arance A. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021 Mar;32(3):384-394. Epub 2020 Dec 10. [https://doi.org/10.1016/j.annonc.2020.12.004 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33309774/ PubMed] [https://clinicaltrials.gov/study/NCT03273153 NCT03273153]
+#'''MASTERKEY-265:''' Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. Epub 2022 Aug 23. [https://doi.org/10.1200/jco.22.00343 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870217/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35998300/ PubMed] [https://clinicaltrials.gov/study/NCT02263508 NCT02263508]
-#Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. [https://www.ejcancer.com/article/S0959-8049(98)00068-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/9849419 PubMed]
+==Temozolomide & Bevacizumab {{#subobject:511376|Regimen=1}}==
-#Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. [https://doi.org/10.1093/annonc/mdl007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16469753 PubMed]
+TB: '''<u>T</u>'''emozolomide & '''<u>B</u>'''evacizumab
+<div class="toccolours" style="background-color:#eeeeee">
-==Dacarbazine monotherapy {{#subobject:d3599b|Regimen=1}}==
+===Regimen {{#subobject:42ead6|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Example orders===
-*[[Example orders for Dacarbazine (DTIC) in melanoma]]
-===Regimen variant #1, 850 mg/m<sup>2</sup> q3wk {{#subobject:b6dcb|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://pubmed.ncbi.nlm.nih.gov/7459898 Pritchard et al. 1980]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)]
-|NR in abstract
+|2008-2010
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
-| style="background-color:#d3d3d3" |
+|[[#ABC|ABC]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#fc8d59" |Seems to have inferior PFS6 (primary endpoint)
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
-*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
-'''21-day cycle for 8 cycles'''
+'''28-day cycles'''
+</div></div>
-===Regimen variant #3, 900 mg/m<sup>2</sup> q3wk {{#subobject:a17084|Variant=1}}===
+===References===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+<!-- This study was presented at the American Society for Clinical Oncology 2011 Annual Meeting, June 3 to 7, Chicago, Illinois, as a poster discussion. -->
-! style="width: 20%" |Study
+#'''N0775:''' Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [https://doi.org/10.1002/cncr.27760 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22915053/ PubMed] [https://clinicaltrials.gov/study/NCT00626405 NCT00626405]
-! style="width: 20%" |Years of enrollment
+=Maintenance after first-line therapy=
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+==IL-2 & GM-CSF {{#subobject:fa72a9|Regimen=1}}==
-! style="width: 20%" |Comparator
+===Example orders===
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+*[[Example orders for IL-2 maintenance biotherapy in melanoma]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:2ed5d3|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598549/ Daponte et al. 2013 (SICOG 0109)]
+|[http://clincancerres.aacrjournals.org/content/8/9/2775.long O'Day et al. 2002]
-|2002-2007
+|1998-2000
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#91cf61" |Phase 2
-|1. Dacarbazine & Fotemustine<br> 2. Dacarbazine & IFN<br> 3. Dacarbazine, Fotemustine, IFN
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+''Note: timing below is based on the assumption that all cycles begin on a Monday.''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Induction [[Regimen_classes#Biochemotherapy|biochemotherapy]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy, low-dose portion (cycles 1, 4, 7, 9, 11)====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 1,000,000 units/m<sup>2</sup> SC once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26
+====Growth factor therapy, low-dose portion (cycles 1, 4, 7, 9, 11)====
+*[[Sargramostim (Leukine)]] 125 mcg/m<sup>2</sup> SC once per day on days 1 to 14
+====Immunotherapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 18,000,000 units/m<sup>2</sup> IV continuous infusion over 6 hours, started on day 1, then 18,000,000 units/m<sup>2</sup> IV continuous infusion over 12 hours, then 18,000,000 units/m<sup>2</sup> IV continuous infusion over 24 hours, then 1,000,000 units/m<sup>2</sup> SC once per day on days 3 to 5, 8 to 12, 15 to 19, 22 to 26
+====Growth factor therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)====
+*[[Sargramostim (Leukine)]] 125 mcg/m<sup>2</sup> SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)
+====Supportive therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)====
+*One of the following 5-HT3 agonists:
+**[[Ondansetron (Zofran)]] 32 mg IV once per day
+**[[Granisetron]] 2 mg IV once per day
+*[[Omeprazole (Prilosec)]] 20 mg PO once every evening
+*[[Acetaminophen (Tylenol)]] 650 mg PO once every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
+*[[Meperidine (Demerol)]] 25 mg IV once every 6 hours as needed for chills and rigors
+'''28-day cycle for 12 cycles'''
+</div></div>
+===References===
+#O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. [http://clincancerres.aacrjournals.org/content/8/9/2775.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12231516/ PubMed]
-*[[Dacarbazine (DTIC)]] 900 mg/m<sup>2</sup> IV once on day 1
+=Metastatic or unresectable disease, second-line=
+==Carboplatin & Paclitaxel (CP) {{#subobject:610571|Regimen=1}}==
-'''21-day cycles'''
+CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel
+<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin
-===Regimen variant #4, 1000 mg/m<sup>2</sup> q3wk {{#subobject:bede4c|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+===Regimen variant #1, AUC 2/100 {{#subobject:5edf1c|Variant=1}}===
-! style="width: 20%" |Study
+{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 20%" |Years of enrollment
+! style="width: 25%" |Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1002/cncr.21611 Rao et al. 2006]
+| style="background-color:#ffffbe" |Retrospective
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15
+*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+'''28-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, AUC 6/175 {{#subobject:06b48b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.1999.17.9.2745 Chapman et al. 1999]
+|[https://doi.org/10.1016/S1470-2045(15)70076-8 Weber et al. 2015 (CheckMate 037)]
-|1991-1997
+|2012-2014
 | style="background-color:#1a9851" |Phase 3 (C)
-|Dartmouth regimen
+|[[#Nivolumab_monotherapy_3|Nivolumab]]
-| style="background-color:#fee08b" |Might have inferior ORR
+| style="background-color:#d73027" |Inferior ORR
 |-
-|[https://doi.org/10.1200/JCO.2007.11.9941 Testori et al. 2008 (C-100-21)]
+|}
-|2002-2004
+''Note: this study did not meet the co-primary endpoint of OS.''
-| style="background-color:#1a9851" |Phase 3 (C)
+<div class="toccolours" style="background-color:#fdcdac">
-|Vitespen
+====Prior treatment criteria====
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+*CheckMate 037, BRAF WT: Exposure to ipilimumab
-|-
+*CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303777/ Bedikian et al. 2010]
+</div>
-|2002-2007
+<div class="toccolours" style="background-color:#b3e2cd">
-| style="background-color:#1a9851" |Phase 3 (C)
+====Chemotherapy====
-|DHA-paclitaxel
+*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, AUC 6/225 x 4, then AUC 5/175 {{#subobject:6a83f2|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ejcancer.com/article/S0959-8049(11)00309-1/fulltext Patel et al. 2011 (EORTC 18032)]
+|[https://doi.org/10.1200/jco.2007.15.7636 Hauschild et al. 2009 (Bayer 11718)]
-|2004-2007
+|2005-05 to 2006-05
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Temozolomide_monotherapy|Temozolomide]]
+|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ Ribas et al. 2013 (A3671009)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)]
-|2006-2007
+|2005-2008
 | style="background-color:#1a9851" |Phase 3 (C)
-|Tremelimumab
+|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652683/ Ugurel et al. 2017 (ChemoSensMM)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
-|2008-2012
+|2012-11-30 to 2013-11-13
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|Chemosensitivity-directed therapy
+|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#d73027" |Inferior PFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ Hersh et al. 2015 (CA033)]
+|}
-|2009-2011
+<div class="toccolours" style="background-color:#fdcdac">
-| style="background-color:#1a9851" |Phase 3 (C)
+====Prior treatment criteria====
-|[[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
+*Bayer 11718: Exposure to a [[Regimen_classes#Dacarbazine-based_regimen|dacarbazine-]] or [[Regimen_classes#Temozolomide-based_regimen|temozolomide-containing regimen]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
+*ECOG E2603: No chemotherapy or [[:Category:MEK_inhibitors|MAP kinase pathway–targeted drugs]]
-|-
+</div>
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)]
+<div class="toccolours" style="background-color:#b3e2cd">
-|2012-2014
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Nivolumab_monotherapy_3|Nivolumab]]
-| style="background-color:#d73027" |Inferior ORR
-|-
-|}
-''Note: CheckMate 037 did not meet the co-primary endpoint of OS.''
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] as follows:
-*[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
+**Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, '''given second'''
+**Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, '''given second'''
-'''21-day cycles'''
+*[[Paclitaxel (Taxol)]] as follows:
+**Cycles 1 to 4: 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-===Regimen variant #5, 1000 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:3f3475|Variant=1}}===
+**Cycle 5 up to 10: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+'''21-day cycle for up to 10 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 200/100, 6 out of 8 weeks {{#subobject:64b1c2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.1998.16.5.1743 Falkson et al. 2003 (ECOG E3690)]
+|[https://doi.org/10.1097/00008390-200310000-00012 Zimpfer-Rechner et al. 2003]
-|NR
+|1998-2000
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-|1. DTIC & Interferon<br> 2. [[Melanoma_-_historical#Dacarbazine_.26_Tamoxifen|DTIC & Tamoxifen]]<br> 3. DTIC, Interferon, Tamoxifen
+|[[#Paclitaxel_monotherapy|Paclitaxel]]
-| style="background-color:#fc8d59" |Seems to have inferior ORR
+| style="background-color:#ffffbf" |Did not meet primary efficacy endpoints
 |-
 |}
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Carboplatin (Paraplatin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
+*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
+'''8-week cycles'''
+</div></div>
+===References===
+#Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. [https://doi.org/10.1097/00008390-200310000-00012 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/14512795/ PubMed]
+#'''Retrospective:''' Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. [https://doi.org/10.1002/cncr.21611 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16342250/ PubMed]
+<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. -->
+#'''Bayer 11718:''' Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. [https://doi.org/10.1200/jco.2007.15.7636 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19349552/ PubMed] [https://clinicaltrials.gov/study/NCT00111007 NCT00111007]
+#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70076-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25795410/ PubMed] [https://clinicaltrials.gov/study/NCT01721746 NCT01721746]
+##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804912/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28671856/ PubMed]
+#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
+##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
+##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
-*[[Dacarbazine (DTIC)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
+==Carboplatin & nab-Paclitaxel {{#subobject:a013af|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''28-day cycles'''
+===Regimen {{#subobject:d78d72|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-===Regimen variant #6, 1250 mg/m<sup>2</sup>, split doses, q3wk {{#subobject:4bacb|Variant=1}}===
+! style="width: 33%" |Study
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 33%" |Dates of enrollment
-! style="width: 20%" |Study
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/10.1056/NEJM199208203270803 Cocconi et al. 1992]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ Kottschade et al. 2011 (N057E1)]
-|1983-1988
+|2006-2007
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#91cf61" |Phase 2
-|[[Melanoma_-_historical#Dacarbazine_.26_Tamoxifen|Dacarbazine & Tamoxifen]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
-|[https://doi.org/10.1200/jco.2000.18.1.158 Middleton et al. 2000b]
+|}
-|1995-1997
+<div class="toccolours" style="background-color:#b3e2cd">
-| style="background-color:#1a9851" |Phase 3 (C)
+====Chemotherapy====
-|[[#Temozolomide_monotherapy|Temozolomide]]
+*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, '''given second'''
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
+====Supportive therapy====
+*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
+'''28-day cycle for up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
+</div></div>
+===References===
+#'''N057E1:''' Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. [https://doi.org/10.1002/cncr.25659 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21472717/ PubMed] [https://clinicaltrials.gov/study/NCT00404235 NCT00404235]
+==Lifileucel & IL-2 {{#subobject:f33e1b|Regimen=1}}==
+TILs: '''<u>T</u>'''umor '''<u>I</u>'''nfiltrating '''<u>L</u>'''ymphocyte'''<u>s</u>'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:12350b|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376325/ Sarnaik et al. 2021 (C-144-01)]
+|2017-2019
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Chimeric_antigen_receptor_T_cells_(CAR-T)#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] lymphodepletion
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Lifileuecel (Contego)]] administered 24 hours after last dose of fludarabine
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 to 12 hours as tolerated for up to 6 doses, starting 3 to 24 hours after completing lifileucel infusion
+</div></div>
+===References===
+# '''C-144-01:''' Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. Epub 2021 May 12. Erratum in: J Clin Oncol. 2021 Sep 10;39(26):2972. [https://doi.org/10.1200/jco.21.00612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33979178/ PubMed] [https://clinicaltrials.gov/study/NCT02360579 NCT02360579]
-*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
+==Toripalimab monotherapy {{#subobject:cbc31b|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''21-day cycles'''
+===Regimen {{#subobject:acb46b|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-===Regimen variant #7, 1250 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:f3110c|Variant=1}}===
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://clinicaltrials.gov/study/NCT03013101 Awaiting publication (Junshi-JS001-BJZL-II)]
+|2016-NR
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Toripalimab (Loqtorzi)]] 3 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div>
+===References===
+#'''Junshi-JS001-BJZL-II:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03013101 NCT03013101]
+=Metastatic or unresectable disease=
+''Note: these regimens have not yet been classified by line of treatment.''
+==Dacarbazine monotherapy {{#subobject:d3599b|Regimen=1}}==
+===Example orders===
+*[[Example orders for Dacarbazine (DTIC) in melanoma]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 850 mg/m<sup>2</sup> q3wk {{#subobject:b6dcb|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://pubmed.ncbi.nlm.nih.gov/7459898 Pritchard et al. 1980]
+|NR in abstract
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 8 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 1000 mg/m<sup>2</sup> q3wk {{#subobject:bede4c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2004.04.165 Avril et al. 2004]
+|[https://doi.org/10.1016/j.ejca.2011.04.030 Patel et al. 2011 (EORTC 18032)]
-|1998-2000
+|2004-2007
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temozolomide_monotherapy|Temozolomide]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
+|2012-11-30 to 2013-11-13
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
+| style="background-color:#d73027" |Inferior PFS
+|-
+|[https://doi.org/10.1016/S1470-2045(15)70076-8 Weber et al. 2015 (CheckMate 037)]
+|2012-2014
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Fotemustine_monotherapy|Fotemustine]]
+|[[#Nivolumab_monotherapy_3|Nivolumab]]
-| style="background-color:#fc8d59" |Seems to have inferior ORR
+| style="background-color:#d73027" |Inferior ORR
 |-
 |}
+''Note: CheckMate 037 did not meet the co-primary endpoint of OS.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*CheckMate 037, BRAF WT: Exposure to ipilimumab
+*CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
+===Regimen variant #3, 1250 mg/m<sup>2</sup>, split doses, q3wk {{#subobject:4bacb|Variant=1}}===
-'''28-day cycles'''
-===Regimen variant #8, 2500 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:ac310c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.1984.2.3.164 Luikart et al. 1984]
+|[https://doi.org/10.1056/NEJM199208203270803 Cocconi et al. 1992]
-|NR
+|1983-1988
 | style="background-color:#1a9851" |Phase 3 (C)
-|BVP
+|[[Melanoma_-_historical#Dacarbazine_.26_Tamoxifen|Dacarbazine & Tamoxifen]]
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Cocconi et al. 1992: No previous treatment with dacarbazine or tamoxifen
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 2500 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:ac310c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.1984.2.3.164 Luikart et al. 1984]
+|NR
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#BVP_999|BVP]]
+| style="background-color:#ffffbf" |Did not meet efficacy endpoints
+|-
+|}
+''Note: This is the first phase 3 RCT published in the Journal of Clinical Oncology.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 10
 '''28-day cycles'''
+</div></div>
 ===References===
+#Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. [https://pubmed.ncbi.nlm.nih.gov/7459898/ PubMed]
-#Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. [https://pubmed.ncbi.nlm.nih.gov/7459898 PubMed]
+#Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. [https://doi.org/10.1200/JCO.1984.2.3.164 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6199481/ PubMed]
-#Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. [https://doi.org/10.1200/JCO.1984.2.3.164 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/6199481 PubMed]
+#Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. [https://doi.org/10.1056/NEJM199208203270803 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1635566/ PubMed]
-#Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. [https://www.nejm.org/doi/10.1056/NEJM199208203270803 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1635566 PubMed]
+#'''EORTC 18032:''' Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; [[Study_Groups#EORTC|EORTC]] Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. [https://doi.org/10.1016/j.ejca.2011.04.030 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21600759/ PubMed] [https://clinicaltrials.gov/study/NCT00091572 NCT00091572]
-#'''ECOG E3690:''' Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; [[Study_Groups#ECOG|ECOG]]. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. [https://doi.org/10.1200/jco.1998.16.5.1743 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9586887 PubMed]
+#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70076-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25795410/ PubMed] [https://clinicaltrials.gov/study/NCT01721746 NCT01721746]
-#Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. [https://doi.org/10.1200/jco.1999.17.9.2745 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10561349 PubMed]
+##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804912/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28671856/ PubMed]
-#Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [https://doi.org/10.1200/jco.2000.18.1.158 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10623706 PubMed]
+#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
-#Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. [https://doi.org/10.1200/JCO.2004.04.165 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15020614 PubMed]
+##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
-#'''C-100-21:''' Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. [https://doi.org/10.1200/JCO.2007.11.9941 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/18281670 PubMed]
+##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
-#Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. [https://doi.org/10.1093/annonc/mdq438 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303777/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20855467 PubMed]
-#'''EORTC 18032:''' Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; [[Study_Groups#EORTC|EORTC]] Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. [https://www.ejcancer.com/article/S0959-8049(11)00309-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21600759 PubMed] NCT00091572
-<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and 25th Annual Meeting of the International Society for Biological Therapy of Cancer, Washington, DC, October 2-4, 2010. -->
-#'''A3671009:''' Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. [https://doi.org/10.1200/JCO.2012.44.6112 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23295794 PubMed] NCT00257205
-#'''SICOG 0109:''' Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-38 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598549/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23402397 PubMed] NCT01359956
-#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25795410 PubMed] NCT01721746
-##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28671856 PubMed]
-#'''CA033:''' Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. [https://doi.org/10.1093/annonc/mdv324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26410620 PubMed] NCT00864253
-#'''ChemoSensMM:''' Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. [http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path []=18635 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652683/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29100289 PubMed] NCT00779714
 ==Docetaxel monotherapy {{#subobject:bd3e54|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:46549|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 33%"|Dates of enrollment
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://doi.org/10.1016/0959-8049(94)90456-1 Aamdal et al. 1994]
-|NR in abstract
+|NR
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+====Supportive therapy====
-====Supportive medications====
 *"No prophylactic treatment with steroids or antihistamines was given."
 '''21-day cycles'''
+</div></div>
 ===References===
+#Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J; [[Study_Groups#EORTC|EORTC]] Early Clinical Trials Group. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. [https://doi.org/10.1016/0959-8049(94)90456-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7654429/ PubMed]
-#Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J; [[Study_Groups#EORTC|EORTC]] Early Clinical Trials Group. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. [https://doi.org/10.1016/0959-8049(94)90456-1 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7654429 PubMed]
+==High-dose Interleukin-2 {{#subobject:771c23|Regimen=1}}==
+HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
-==Fotemustine monotherapy {{#subobject:92d0c6|Regimen=1}}==
+===Example orders===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Example orders for High-dose (HD) IL-2 in melanoma]]
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
+===Regimen variant #1, 600k, up to 3 cycles {{#subobject:4efbce|Variant=1}}===
-|}
-===Regimen {{#subobject:ff4f50|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2004.04.165 Avril et al. 2004]
+|[https://doi.org/10.1200/JCO.1993.11.10.1969 Sparano et al. 1993]
-|1998-2000
+|NR
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
+|[[#High-dose_Interleukin-2_.26_Interferon_alfa-2a_999|HD IL-2 & IFN alfa-2a]]
-| style="background-color:#91cf60" |Seems to have superior ORR
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
 |}
-====Chemotherapy====
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Fotemustine (Muphoran)]] as follows:
+====Immunotherapy====
-**Weeks 1 to 3: 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 28 total doses per cycle)
-**Weeks 4 to 8: no treatment
+====Supportive therapy====
-**Week 9 onwards: 100 mg/m<sup>2</sup> IV once on day 1, every 3 weeks
+*Included:
+*[[Acetaminophen (Tylenol)]]
-'''8-week induction cycle, then 21-day cycles'''
+*[[Indomethacin (Indocin)]]
+*[[Meperidine (Demerol)]]
-===References===
+*[[Ranitidine (Zantac)]]
+*[[Cimetidine (Tagamet)]]
-#Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. [https://doi.org/10.1200/JCO.2004.04.165 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15020614 PubMed]
+*[[Hydroxyzine (Atarax)]]
+*[[Diphenhydramine (Benadryl)]]
-==High-dose Interleukin-2 {{#subobject:771c23|Regimen=1}}==
+*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
-{| class="wikitable" style="float:right; margin-left: 5px;"
+'''12-week cycle for up to 3 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 600k, up to 5 cycles {{#subobject:4ehg1e|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1200/jco.1999.17.7.2105 Atkins et al. 1999]
+|1985-1993
+| style="background-color:#91cf61" |Phase 2 (RT)
 |-
-|[[#top|back to top]]
 |}
-HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
+<div class="toccolours" style="background-color:#b3e2cd">
-===Example orders===
+====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
-*[[Example orders for High-dose (HD) IL-2 in melanoma]]
+**After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above
+====Supportive therapy====
-===Regimen variant #1, 600k, up to 3 cycles {{#subobject:4efbce|Variant=1}}===
+*Included:
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+*[[Acetaminophen (Tylenol)]]
-! style="width: 20%" |Study
+*[[Indomethacin (Indocin)]]
-! style="width: 20%" |Years of enrollment
+*[[Meperidine (Demerol)]]
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Ranitidine (Zantac)]]
-! style="width: 20%" |Comparator
+*[[Cimetidine (Tagamet)]]
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+*[[Hydroxyzine (Atarax)]]
+*[[Diphenhydramine (Benadryl)]]
+*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
+'''6- to 12-week cycle for up to 5 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 720k, up to 3 cycles {{#subobject:4efbce|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/JCO.1993.11.10.1969 Sparano et al. 1993]
+|[http://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
-|NR
+|1985-1992
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#91cf61" |Non-randomized
-|HD IL-2 & IFN alfa-2a
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 30 total doses per cycle)
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 28 total doses per cycle)
+====Supportive therapy====
-====Supportive medications====
 *Included:
 *[[Acetaminophen (Tylenol)]]
@@ Line 1,666: / Line 1,997: @@
 *[[Diphenhydramine (Benadryl)]]
 *Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
+'''2-month cycle for up to 3 cycles'''
-'''12-week cycle for up to 3 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 600k, up to 5 cycles {{#subobject:4ehg1e|Variant=1}}===
+===Regimen variant #4, 720k, up to 5 cycles {{#subobject:4jbaq1|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 ! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
+! style="width: 33%" |Dates of enrollment
 ! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
 |[https://doi.org/10.1200/jco.1999.17.7.2105 Atkins et al. 1999]
 |1985-1993
-| style="background-color:#91cf61" |Phase II (RT)
+| style="background-color:#91cf61" |Phase 2 (RT)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
 **After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above
+====Supportive therapy====
-====Supportive medications====
 *Included:
 *[[Acetaminophen (Tylenol)]]
@@ Line 1,696: / Line 2,025: @@
 *[[Diphenhydramine (Benadryl)]]
 *Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
 '''6- to 12-week cycle for up to 5 cycles'''
+</div></div><br>
-===Regimen variant #3, 720k, up to 3 cycles {{#subobject:4efbce|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+===Regimen variant #5, 720k, indefinite {{#subobject:61ghce|Variant=1}}===
-! style="width: 33%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 33%" |Years of enrollment
+! style="width: 20%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517182/ Schwartzentruber et al. 2011 (NCI-2012-02897)]
-|1985-1992
+|2000-2007
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#High-dose_Interleukin-2_.26_gp100_vaccine_888|HD IL-2 & gp100 vaccine]]
+| style="background-color:#fc8d59" |Seems to have inferior clinical response
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours as tolerated on days 1 to 4, 22 to 25 (up to 24 total doses per cycle)
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 30 total doses per cycle)
+====Supportive therapy====
-====Supportive medications====
 *Included:
 *[[Acetaminophen (Tylenol)]]
@@ Line 1,726: / Line 2,057: @@
 *[[Diphenhydramine (Benadryl)]]
 *Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
+'''7-week cycles'''
-'''2-month cycle for up to 3 cycles'''
+</div></div>
+===References===
-===Regimen variant #4, 720k, up to 5 cycles {{#subobject:4jbaq1|Variant=1}}===
+#Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. [https://doi.org/10.1200/JCO.1993.11.10.1969 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8410122/ PubMed]
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [http://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8120958/ PubMed]
-! style="width: 33%" |Study
+#Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. [https://doi.org/10.1200/jco.1999.17.7.2105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561265/ PubMed]
-! style="width: 33%" |Years of enrollment
+##'''Update:''' Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. [https://pubmed.ncbi.nlm.nih.gov/10685652/ PubMed]
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+#'''NCI-2012-02897:''' Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011 Jun 2;364(22):2119-27. [https://doi.org/10.1056/NEJMoa1012863 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517182/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21631324/ PubMed] [https://clinicaltrials.gov/study/NCT00019682 NCT00019682]
-|-
+==Ipilimumab monotherapy {{#subobject:fab3f4|Regimen=1}}==
-|[https://doi.org/10.1200/jco.1999.17.7.2105 Atkins et al. 1999]
+===Example orders===
-|1985-1993
+*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
-| style="background-color:#91cf61" |Phase II (RT)
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 3 mg/kg {{#subobject:33786a|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
 |}
-====Immunotherapy====
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
+! style="width: 20%" |Dates of enrollment
-**After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above
-====Supportive medications====
-*Included:
-*[[Acetaminophen (Tylenol)]]
-*[[Indomethacin (Indocin)]]
-*[[Meperidine (Demerol)]]
-*[[Ranitidine (Zantac)]]
-*[[Cimetidine (Tagamet)]]
-*[[Hydroxyzine (Atarax)]]
-*[[Diphenhydramine (Benadryl)]]
-*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
-'''6- to 12-week cycle for up to 5 cycles'''
-===Regimen variant #5, 720k, indefinite {{#subobject:61ghce|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517182/ Schwartzentruber et al. 2011 (NCI-2012-02897)]
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ Hodi et al. 2010 (MDX010-20)]
-|2000-2007
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (C)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-81-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-|HD IL-2 & gp100 vaccine
-| style="background-color:#fc8d59" |Seems to have inferior clinical response
 |-
-|}
+|} -->
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+| rowspan="2" |2004-2008
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1. [[#Ipilimumab_.26_gp100_vaccine_999|Ipilimumab & gp100 peptide vaccine]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|2. [[#gp100_vaccine_888|gp100 peptide vaccine]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10 vs 6.4 mo<br>(HR 0.68, 95% CI 0.55-0.85)
+|-
+|[https://doi.org/10.1016/S1470-2045(17)30231-0 Ascierto et al. 2017 (CA184-169)]
+|2012-02-29 to 2012-07-09
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Ipilimumab_monotherapy_3|Ipilimumab]]; 10 mg/kg
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
+| rowspan="2" |2013-09-18 to 2014-03-03
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q2wks
+| style="background-color:#d73027" |Inferior OS
+|-
+|2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wks
+| style="background-color:#d73027" |Inferior OS
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] 3 mg/kg IV over 90 minutes once on day 1
+'''21-day cycle for 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours as tolerated on days 1 to 4, 22 to 25 (up to 24 total doses per cycle)
+===Regimen variant #2, 10 mg/kg limited duration {{#subobject:7e975b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Supportive medications====
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-*Included:
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Acetaminophen (Tylenol)]]
+! style="width: 20%" |Comparator
-*[[Indomethacin (Indocin)]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*[[Meperidine (Demerol)]]
+|-
-*[[Ranitidine (Zantac)]]
+|[https://doi.org/10.1200/JCO.2008.16.1927 Weber et al. 2008]
-*[[Cimetidine (Tagamet)]]
+|2003-2005
-*[[Hydroxyzine (Atarax)]]
+| style="background-color:#91cf61" |Phase 1/2
-*[[Diphenhydramine (Benadryl)]]
+| style="background-color:#d3d3d3" |
-*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
+| style="background-color:#d3d3d3" |
+|-
-'''7-week cycles'''
+|[https://doi.org/10.1016/S1470-2045%2809%2970334-1 Wolchok et al. 2010 (CA184-022)]
+|2006-2007
-===References===
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
-#Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. [https://doi.org/10.1200/JCO.1993.11.10.1969 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8410122 PubMed]
+| style="background-color:#d3d3d3" |
-#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [http://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8120958 PubMed]
+|-
-#Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. [https://doi.org/10.1200/jco.1999.17.7.2105 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10561265 PubMed]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336189/ Hodi et al. 2014 (ECOG E1608)]
-##'''Update:''' Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. [https://pubmed.ncbi.nlm.nih.gov/10685652 PubMed]
+|2010-2011
-#'''NCI-2012-02897:''' Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011 Jun 2;364(22):2119-27. [https://www.nejm.org/doi/full/10.1056/NEJMoa1012863 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517182/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21631324 PubMed] NCT00019682
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#Ipilimumab_.26_Sargramostim_888|Ipilimumab & GM-CSF]]
-==Ipilimumab monotherapy {{#subobject:fab3f4|Regimen=1}}==
+| style="background-color:#d73027" |Inferior OS
-{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[https://doi.org/10.1016/S1470-2045(17)30231-0 Ascierto et al. 2017 (CA184-169)]
+|2012-02-29 to 2012-07-09
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Ipilimumab_monotherapy_3|Ipilimumab]]; 3 mg/kg
+| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 15.7 vs 11.5 mo<br>(HR 0.84, 95% CI 0.71-0.99)
 |-
-|[[#top|back to top]]
 |}
+''<sup>1</sup>Reported efficacy is based on the 2020 update.''<br>
-===Example orders===
+''Note: In CA184-022, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
-===Regimen variant #1, 3 mg/kg {{#subobject:33786a|Variant=1}}===
+'''21-day cycle for 4 cycles'''
-{| class="wikitable" style="color:white; background-color:#404040"
+</div></div><br>
-|<small>'''FDA-recommended dose'''</small>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 10 mg/kg with maintenance {{#subobject:7e98hgv|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|}
+|[https://doi.org/10.1093/annonc/mdq013 O'Day et al. 2010 (CA184-008)]
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+|2006-2007
-! style="width: 20%" |Study
+| style="background-color:#91cf61" |Phase 2
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ Hodi et al. 2010 (MDX010-20)]
+|[https://doi.org/10.1016/S1470-2045(12)70090-6 Margolin et al. 2012 (CA184-042)]
-| rowspan="2" |2004-2008
+|2008-2009
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+| style="background-color:#91cf61" |Phase 2
-|1. Ipilimumab & gp100 peptide vaccine
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|2. gp100 peptide vaccine
+|}
-| style="background-color:#1a9850" |Superior OS
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
+'''21-day cycle for 4 cycles, then 12-week cycles'''
+</div></div>
+===References===
+#Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. [https://doi.org/10.1200/JCO.2008.16.1927 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19018089/ PubMed]
+#'''CA184-022:''' Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. [https://doi.org/10.1016/S1470-2045%2809%2970334-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20004617/ PubMed] [https://clinicaltrials.gov/study/NCT00289640 NCT00289640]
+#'''MDX010-20:''' Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. [https://doi.org/10.1056/NEJMoa1003466 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20525992/ PubMed] [https://clinicaltrials.gov/study/NCT00094653 NCT00094653]
+##'''HRQoL analysis:''' Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012 Jun 13;10:66. [https://doi.org/10.1186/1477-7525-10-66 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3426458/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22694829/ PubMed]
+##'''Subgroup analysis:''' McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. [https://doi.org/10.1093/annonc/mdt291 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23942774/ PubMed]
+#'''CA184-008:''' O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. [https://doi.org/10.1093/annonc/mdq013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20147741/ PubMed] [https://clinicaltrials.gov/study/NCT00289627 NCT00289627]
+#'''CA184-042:''' Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. [https://doi.org/10.1016/S1470-2045(12)70090-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22456429/ PubMed] [https://clinicaltrials.gov/study/NCT00623766 NCT00623766]
+#'''ECOG E1608:''' Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. [https://jamanetwork.com/journals/jama/fullarticle/1920969 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336189/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25369488/ PubMed] [https://clinicaltrials.gov/study/NCT01134614 NCT01134614]
+#'''KEYNOTE-006:''' Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. [https://doi.org/10.1056/NEJMoa1503093 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25891173/ PubMed] [https://clinicaltrials.gov/study/NCT01866319 NCT01866319]
+##'''Update:''' Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. [https://doi.org/10.1016/S0140-6736(17)31601-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/28822576/ PubMed]
+##'''PRO analysis:''' Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. [https://doi.org/10.1016/j.ejca.2017.08.032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28987768/ PubMed]
+##'''Update:''' Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. [https://doi.org/10.1016/S1470-2045(19)30388-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345627/ PubMed]
+##'''Update:''' Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. [https://doi.org/10.1200/jco.22.01599 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37348035/ PubMed]
+#'''CA184-169:''' Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. [https://doi.org/10.1016/S1470-2045(17)30231-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28359784/ PubMed] [https://clinicaltrials.gov/study/NCT01515189 NCT01515189]
+##'''Update:''' Ascierto PA, Del Vecchio M, Mackiewicz A, Robert C, Chiarion-Sileni V, Arance A, Lebbé C, Svane IM, McNeil C, Rutkowski P, Loquai C, Mortier L, Hamid O, Bastholt L, Dreno B, Schadendorf D, Garbe C, Nyakas M, Grob JJ, Thomas L, Liszkay G, Smylie M, Hoeller C, Ferraresi V, Grange F, Gutzmer R, Pikiel J, Hosein F, Simsek B, Maio M. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer. 2020 Jun;8(1):e000391. Erratum in: J Immunother Cancer. 2020 Jul;8(2). [https://doi.org/10.1136/jitc-2019-000391 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7279645/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32503946/ PubMed]
+#'''M14TIL:''' [https://clinicaltrials.gov/study/NCT02278887 NCT02278887]
+==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:fa55a8|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30231-0/fulltext Ascierto et al. 2017 (CA184-169)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698004/ Wolchok et al. 2013 (CheckMate 004)]
-|2012
+|2009-2013
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#ffffbe" |Phase 1
-|[[#Ipilimumab_monotherapy_3|Ipilimumab]]; 10 mg/kg
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
-| rowspan="2" |2013-2014
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q2wks
-| style="background-color:#d73027" |Inferior OS
-|-
-|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q3wks
-| style="background-color:#d73027" |Inferior OS
 |-
 |}
+''Note: These doses were from the cohort deemed by CheckMate 004 as being "the maximum doses that were associated with an acceptable level of adverse events."''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] as follows:
+**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given second'''
+*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, '''given first'''
+'''21-day cycle for 8 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Ipilimumab_.26_Nivolumab_3|Ipilimumab & nivolumab]] maintenance
+</div></div>
+===References===
+#'''CheckMate 004:''' Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. Epub 2013 Jun 2. [https://doi.org/10.1056/NEJMoa1302369 link to original article] '''contains dosing details in manuscript''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1302369/suppl_file/nejmoa1302369_appendix.pdf link to supplementary appendix] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698004/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23724867/ PubMed] [https://clinicaltrials.gov/study/NCT01024231 NCT01024231]
-*[[Ipilimumab (Yervoy)]] 3 mg/kg IV over 90 minutes once on day 1
+==Ipilimumab-Nivolumab {{#subobject:184810|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''21-day cycle for 4 cycles'''
+===Regimen {{#subobject:8347ab|Variant=1}}===
-===Regimen variant #2, 10 mg/kg {{#subobject:7e975b|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2008.16.1927 Weber et al. 2008]
+|[https://doi.org/10.1016/S1470-2045(16)30126-7 Weber et al. 2016 (CheckMate 064)]
-|2003-2005
+|2013-2014
-| style="background-color:#91cf61" |Phase I/II
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
-| style="background-color:#d3d3d3" |
+|[[#Nivolumab-Ipilimumab|Nivolumab, then Ipilimumab]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#d73027" |Inferior OS (secondary endpoint)
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970334-1/fulltext Wolchok et al. 2010 (CA184-022)]
-|2006-2007
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1093/annonc/mdq013 O'Day et al. 2010 (CA184-008)]
-|2006-2007
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70090-6/abstract Margolin et al. 2012 (CA184-042)]
-|2008-2009
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336189/ Hodi et al. 2014 (ECOG E1608)]
-|2010-2011
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|Ipilimumab & Sargramostim
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30231-0/fulltext Ascierto et al. 2017 (CA184-169)]
-|2012
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ipilimumab_monotherapy_3|Ipilimumab]]; 3 mg/kg
-| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br>Median OS: 15.7 vs 11.5 mo<br>(HR 0.84, 95% CI 0.71-0.99)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2020 update.''<br>
+''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
-''Note: In CA184-022, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] as follows:
-*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
+**Cycles 1 to 4: 3 mg/kg IV once on day 1
+*[[Nivolumab (Opdivo)]] as follows:
-'''21-day cycle for 4 cycles'''
+**Cycle 5 onwards: 3 mg/kg IV once on day 1
-====Subsequent treatment====
+'''21-day cycle for 4 cycles, then 14-day cycles'''
+</div></div>
-*CA184-008 & CA184-042: Patients who were clinically stable could proceed to [[#Ipilimumab_monotherapy_4|ipilimumab maintenance]]
 ===References===
+#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://doi.org/10.1016/S1470-2045(16)30126-7 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740/ PubMed] [https://clinicaltrials.gov/study/NCT01783938 NCT01783938]
-#Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. [https://doi.org/10.1200/JCO.2008.16.1927 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19018089 PubMed]
+==Nivolumab monotherapy {{#subobject:6a44dd|Regimen=1}}==
-#'''CA184-022:''' Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970334-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20004617 PubMed] NCT00289640
+<div class="toccolours" style="background-color:#eeeeee">
-#'''MDX010-20:''' Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. [https://www.nejm.org/doi/full/10.1056/NEJMoa1003466 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20525992 PubMed] NCT00094653
+===Regimen variant #1, limited duration {{#subobject:1ec35|Variant=1}}===
-##'''Update:''' McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. [https://doi.org/10.1093/annonc/mdt291 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23942774 PubMed]
-#'''CA184-008:''' O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. [https://doi.org/10.1093/annonc/mdq013 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20147741 PubMed] NCT00289627
-#'''CA184-042:''' Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70090-6/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22456429 PubMed] NCT00623766
-#'''ECOG E1608:''' Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. [https://jamanetwork.com/journals/jama/fullarticle/1920969 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336189/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25369488 PubMed] NCT01134614
-#'''KEYNOTE-006:''' Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1503093 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25891173 PubMed] NCT01866319
-##'''Update:''' Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31601-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28822576 PubMed]
-##'''Update:''' Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30388-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345627 PubMed]
-#'''CA184-169:''' Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30231-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28359784 PubMed] NCT01515189
-##'''Update:''' Ascierto PA, Del Vecchio M, Mackiewicz A, Robert C, Chiarion-Sileni V, Arance A, Lebbé C, Svane IM, McNeil C, Rutkowski P, Loquai C, Mortier L, Hamid O, Bastholt L, Dreno B, Schadendorf D, Garbe C, Nyakas M, Grob JJ, Thomas L, Liszkay G, Smylie M, Hoeller C, Ferraresi V, Grange F, Gutzmer R, Pikiel J, Hosein F, Simsek B, Maio M. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer. 2020 Jun;8(1):e000391. Erratum in: J Immunother Cancer. 2020 Jul;8(2). [https://doi.org/10.1136/jitc-2019-000391 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7279645/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32503946/ PubMed]
-==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1 {{#subobject:fa55a8|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 ! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
+! style="width: 33%" |Dates of enrollment
 ! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698004/ Wolchok et al. 2013 (CheckMate 004)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ Weber et al. 2013 (MCC-15400)]
-|2009-2013
+|2010-2012
 | style="background-color:#ffffbe" |Phase 1
 |-
 |}
-''These doses were from the cohort deemed by CheckMate 004 as being "the maximum doses that were associated with an acceptable level of adverse events."''
+''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data. It is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-*[[Ipilimumab (Yervoy)]] as follows:
+'''14-day cycle for 12 cycles, then 12-week cycle for 8 cycles (see note)'''
-**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given second'''
+</div></div><br>
-*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, '''given first'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, indefinite {{#subobject:722e51|Variant=1}}===
-'''21-day cycle for 8 cycles'''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Subsequent treatment====
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-*[[#Ipilimumab_.26_Nivolumab_3|Ipilimumab & nivolumab maintenance]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(15)70076-8 Weber et al. 2015 (CheckMate 037)]
+|2012-2014
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|Investigator's choice of:<br>1a. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br>1b. [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]]
+| style="background-color:#1a9850" |Superior ORR (co-primary endpoint)
+|-
+|}
+''Note: CheckMate 037 did not meet the co-primary endpoint of OS. On 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*CheckMate 037, BRAF WT: Exposure to ipilimumab
+*CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div>
 ===References===
+#'''MCC-15400:''' Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. Epub 2013 Oct 21. [https://doi.org/10.1200/JCO.2013.51.4802 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24145345/ PubMed] [https://clinicaltrials.gov/study/NCT01176461 NCT01176461]
+#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70076-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25795410/ PubMed] [https://clinicaltrials.gov/study/NCT01721746 NCT01721746]
+##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804912/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28671856/ PubMed]
-#'''Phase I:''' Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. [https://www.nejm.org/doi/full/10.1056/NEJMoa1302369 link to original article] '''contains verified protocol''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1302369/suppl_file/nejmoa1302369_appendix.pdf link to supplementary appendix] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698004/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23724867 PubMed] NCT01024231
+==Nivolumab-Ipilimumab {{#subobject:1145b9|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Ipilimumab, then Nivolumab {{#subobject:184810|Regimen=1}}==
+===Regimen {{#subobject:61d1da|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 17%"|Study
+!style="width: 15%"|Dates of enrollment
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://doi.org/10.1016/S1470-2045(16)30126-7 Weber et al. 2016 (CheckMate 064)]
+|2013-2014
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
+|[[#Ipilimumab-Nivolumab|Ipilimumab, then Nivolumab]]
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: NYR vs 16.9 mo<br>(HR 0.48, 95% CI 0.29-0.80)
+| style="background-color:#eeee01" |Similar rate of grade 3-5 TRAEs (primary endpoint)
 |-
-|[[#top|back to top]]
 |}
-===Protocol {{#subobject:8347ab|Variant=1}}===
+''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] as follows:
+**Cycles 1 to 6: 3 mg/kg IV once on day 1
+**Cycle 11 onwards: 3 mg/kg IV once on day 1
+*[[Ipilimumab (Yervoy)]] as follows:
+**Cycles 7 to 10: 3 mg/kg IV once on day 1
+'''14-day cycle for 6 cycles, then 21-day cycle for 4 cycles, then 14-day cycles'''
+</div></div>
+===References===
+#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://doi.org/10.1016/S1470-2045(16)30126-7 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740/ PubMed] [https://clinicaltrials.gov/study/NCT01783938 NCT01783938]
+==Paclitaxel monotherapy {{#subobject:bfd5b|Regimen=1}}==
+===Example orders===
+*[[Example orders for Paclitaxel (Taxol) in melanoma]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:d13282|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext Weber et al. 2016 (CheckMate 064)]
+|[https://doi.org/10.1200/jco.2012.44.5585 O'Day et al. 2013 (SYMMETRY)]
-|2013-2014
+|2007-2009
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Nivolumab.2C_then_Ipilimumab|Nivolumab, then Ipilimumab]]
+|[[#Elesclomol_.26_Paclitaxel_999|Elesclomol & Paclitaxel]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
-|}
+|[https://doi.org/10.1002/cncr.28635 Hamid et al. 2014 (SUMMIT-1)]
-====Immunotherapy, part 1====
+|2009-NR
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1
+|[[#Tasisulam_monotherapy_999|Tasisulam]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-'''21-day cycle for 4 cycles, followed by:'''
-====Immunotherapy, part 2====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
-'''14-day cycle for 6 cycles'''
-====Subsequent treatment====
-*[[#Nivolumab_monotherapy_4|Nivolumab maintenance]]
-===References===
-#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740 PubMed] NCT01783938
-==Nivolumab monotherapy {{#subobject:6a44dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-===Regimen variant #1, limited duration {{#subobject:1ec35|Variant=1}}===
+''Note: This was the control arm of SYMMETRY, which was a negative study. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+<div class="toccolours" style="background-color:#b3e2cd">
-! style="width: 33%" |Study
+====Chemotherapy====
-! style="width: 33%" |Years of enrollment
+*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+'''28-day cycles'''
-|-
+</div></div><br>
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ Weber et al. 2013 (MCC-15400)]
+<div class="toccolours" style="background-color:#eeeeee">
-|2010-2012
+===Regimen variant #2, 175 mg/m<sup>2</sup> q3wk {{#subobject:2839uq|Variant=1}}===
-| style="background-color:#ffffbe" |Phase I
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
-'''14-day cycle for 12 cycles'''
-====Subsequent treatment====
-*[[#Nivolumab_monotherapy_4|Nivolumab maintenance]]
-===Regimen variant #2, indefinite {{#subobject:722e51|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
-|2012-2014
+|2012-11-30 to 2013-11-13
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|1. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br> 2. [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]
+|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
-| style="background-color:#1a9850" |Superior ORR
+| style="background-color:#d73027" |Inferior PFS
 |-
 |}
-''Note: CheckMate 037 did not meet the co-primary endpoint of OS.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Immunotherapy====
+====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+'''21-day cycles'''
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''14-day cycles'''
+===Regimen variant #3, 250 mg/m<sup>2</sup> q3wk {{#subobject:283bc4|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1002/1097-0142(19900601)65:11%3C2478::AID-CNCR2820651114%3E3.0.CO;2-S Legha et al. 1990]
+|NR
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
+'''21-day cycles'''
+</div></div>
 ===References===
+#Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. [https://doi.org/10.1002/1097-0142(19900601)65:11%3C2478::AID-CNCR2820651114%3E3.0.CO;2-S link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1970948/ PubMed]
+#'''SYMMETRY:''' O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. [https://doi.org/10.1200/jco.2012.44.5585 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23401447/ PubMed] [https://clinicaltrials.gov/study/NCT00522834 NCT00522834]
+#'''SUMMIT-1:''' Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. [https://doi.org/10.1002/cncr.28635 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24676877/ PubMed] [https://clinicaltrials.gov/study/NCT01006252 NCT01006252]
+#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
+##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
+##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
-#'''MCC-15400:''' Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. [https://doi.org/10.1200/JCO.2013.51.4802 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24145345 PubMed] NCT01176461
+==nab-Paclitaxel monotherapy {{#subobject:1748f5|Regimen=1}}==
-#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25795410 PubMed] NCT01721746
+<div class="toccolours" style="background-color:#eeeeee">
-##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28671856 PubMed]
+===Regimen variant #1 {{#subobject:df0a74|Variant=1}}===
-==Nivolumab, then Ipilimumab {{#subobject:1145b9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Protocol {{#subobject:61d1da|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext Weber et al. 2016 (CheckMate 064)]
+|[https://doi.org/10.1002/cncr.24720 Hersh et al. 2012]
-|2013-2014
+|NR
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
+| style="background-color:#91cf61" |Phase 2
-|[[#Ipilimumab.2C_then_Nivolumab|Ipilimumab, then Nivolumab]]
+| style="background-color:#d3d3d3" |
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ Hersh et al. 2015 (CA033)]
+|2009-04 to 2011-06
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 4.8 vs 2.5 mo<br>(HR 0.79, 95.1% CI 0.63-0.99)
 |-
 |}
-====Immunotherapy, part 1====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
+'''28-day cycles'''
+</div></div><br>
-'''14-day cycle for 6 cycles, followed by:'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:f13d6e|Variant=1}}===
-====Immunotherapy, part 2====
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
-*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-'''21-day cycle for 4 cycles'''
+|-
-====Subsequent treatment====
+|[https://doi.org/10.1002/cncr.24720 Hersh et al. 2012]
+|NR
-*[[#Nivolumab_monotherapy_4|Nivolumab maintenance]]
+| style="background-color:#91cf61" |Phase 2
-===References===
-#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740 PubMed] NCT01783938
-==Paclitaxel monotherapy {{#subobject:bfd5b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
 |}
-===Example orders===
+''Note: this dose was intended for previously treated patients.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Example orders for Paclitaxel (Taxol) in melanoma]]
+====Chemotherapy====
+*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-===Regimen variant #1, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:d13282|Variant=1}}===
+'''28-day cycles'''
+</div></div>
+===References===
+#Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. [https://doi.org/10.1002/cncr.24720 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19877111/ PubMed]
+#'''CA033:''' Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. [https://doi.org/10.1093/annonc/mdv324 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26410620/ PubMed] [https://clinicaltrials.gov/study/NCT00864253 NCT00864253]
+==Pembrolizumab monotherapy {{#subobject:78d8cc|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 2 mg/kg q3wk {{#subobject:25a9fe|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2012.44.5585 O'Day et al. 2013 (SYMMETRY)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001<sub>melanoma</sub>)]
-|2007-2009
+|2011-2012
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#91cf61" |Phase 1, >20 pts
-|Elesclomol & Paclitaxel
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-91-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+| rowspan="2" |2012-11-30 to 2013-11-13
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-switch-ooc)
+|Investigator's choice of:<br>1a. [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]]<br>1b. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br>1c. [[#Paclitaxel_monotherapy|Paclitaxel]]<br>1d. [[#Temozolomide_monotherapy|Temozolomide]]
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS6: 34% vs 16%<br>(HR 0.57, 95% CI 0.45-0.73)
+|-
+|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q3wk
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28635 Hamid et al. 2014 (SUMMIT-1)]
-|2009-NR
-| style="background-color:#1a9851" |Phase 3 (C)
-|Tasisulam
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''This was the control arm of SYMMETRY, which was a negative study. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
+<div class="toccolours" style="background-color:#fdcdac">
-====Chemotherapy====
+====Prior treatment criteria====
+*KEYNOTE-002, BRAFwt: Failure of ipilimumab
+*KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 2 mg/kg IV over 30 minutes once on day 1
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+===Regimen variant #2, 10 mg/kg q2wk {{#subobject:2829cd|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-'''28-day cycles'''
-===Regimen variant #2, 250 mg/m<sup>2</sup> q3wk {{#subobject:283bc4|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19900601)65:11%3C2478::AID-CNCR2820651114%3E3.0.CO;2-S Legha et al. 1990]
-|NR
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-'''21-day cycles'''
-===References===
-#Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19900601)65:11%3C2478::AID-CNCR2820651114%3E3.0.CO;2-S link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/1970948 PubMed]
-#'''SYMMETRY:''' O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. [https://doi.org/10.1200/jco.2012.44.5585 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23401447 PubMed] NCT00522834
-#'''SUMMIT-1:''' Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.28635 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24676877 PubMed] NCT01006252
-==nab-Paclitaxel monotherapy {{#subobject:1748f5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1 {{#subobject:df0a74|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24720/abstract Hersh et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001<sub>melanoma</sub>)]
-|NR
+|2011-2012
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#91cf61" |Phase 1, >20 pts
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ Hersh et al. 2015 (CA033)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
-|2009-2011
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-327-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
+|-
-| style="background-color:#91cf60" |Seems to have superior PFS
+|} -->
+| rowspan="2" |2013-09-18 to 2014-03-03
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|1. [[#Ipilimumab_monotherapy_3|Ipilimumab]]
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>OS12: 74.1% vs 58.2%<br>(HR 0.63, 95% CI 0.47-0.83)
+|-
+|2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+*KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease
+</div>
-'''28-day cycles'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-===Regimen variant #2 {{#subobject:f13d6e|Variant=1}}===
+*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+'''14-day cycles'''
-! style="width: 33%" |Study
+</div></div><br>
-! style="width: 33%" |Years of enrollment
+<div class="toccolours" style="background-color:#eeeeee">
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+===Regimen variant #3, 10 mg/kg q3wk {{#subobject:e60ce6|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24720/abstract Hersh et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001<sub>melanoma</sub>)]
-|NR
+|2011-2012
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#91cf61" |Phase 1, >20 pts
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|}
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
-''Note: this dose was intended for previously treated patients.''
+| rowspan="2" |2012-11-30 to 2013-11-13
-====Chemotherapy====
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-switch-ooc)
+|Investigator's choice of:<br>1a. [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]<br>1b. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br>1c. [[#Paclitaxel_monotherapy|Paclitaxel]]<br>1d. [[#Temozolomide_monotherapy|Temozolomide]]
-*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS6: 38% vs 16%<br>(HR 0.50, 95% CI 0.39-0.64)
+|-
-'''28-day cycles'''
+|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 2 mg/kg
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-===References===
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
-#Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24720/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19877111 PubMed]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-#'''CA033:''' Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. [https://doi.org/10.1093/annonc/mdv324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26410620 PubMed] NCT00864253
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-327-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
-==Pembrolizumab monotherapy {{#subobject:78d8cc|Regimen=1}}==
+|} -->
-{| class="wikitable" style="float:right; margin-left: 5px;"
+| rowspan="2" |2013-09-18 to 2014-03-03
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|1. [[#Ipilimumab_monotherapy_3|Ipilimumab]]
+| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>OS12: 68.4% vs 58.2%<br>(HR 0.69, 95% CI 0.52-0.90)
+|-
+|2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q2wk
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
 |-
-|[[#top|back to top]]
 |}
-===Regimen variant #1, 2 mg/kg q3wk {{#subobject:25a9fe|Variant=1}}===
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*KEYNOTE-002, BRAFwt: Failure of ipilimumab
+*KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both
+*KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV over 30 minutes once on day 1
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 200 mg q3wk {{#subobject:e84ce6|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001)]
+|[https://doi.org/10.1016/S1470-2045(19)30274-8 Long et al. 2019 (ECHO-301/KEYNOTE-252)]
-|2011-2012
+|2016-06-21 to 2017-08-07
-| style="background-color:#91cf61" |Phase I, >20 pts
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#d3d3d3" |
+|[[#Epacadostat_.26_Pembrolizumab_999|Epacadostat & Pembrolizumab]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext Ribas et al. 2015 (KEYNOTE-002)]
-| rowspan="2" |2012-2013
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-RT-switch-ooc)
-|Investigator-choice of:<br> 1. [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]<br> 2. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br> 3. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 4. [[#Temozolomide_monotherapy|Temozolomide]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|5. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q3wk
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*ECHO-301/KEYNOTE-252: No previous treatment with PD-1 or PD-L1 checkpoint inhibitors
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+'''21-day cycle for up to 35 cycles (2 years)'''
+</div></div>
+===References===
+#'''KEYNOTE-001<sub>melanoma</sub>:''' Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. [https://doi.org/10.1056/NEJMoa1305133 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23724846/ PubMed] [https://clinicaltrials.gov/study/NCT01295827 NCT01295827]
+##'''Update:''' Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. [https://doi.org/10.1016/S0140-6736(14)60958-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25034862/ PubMed]
+##'''Update:''' Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. [https://jamanetwork.com/journals/jama/fullarticle/2514195 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27092830/ PubMed]
+##'''Update:''' Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. [https://doi.org/10.1093/annonc/mdz011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503622/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30715153/ PubMed]
+#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
+##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
+##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
+#'''KEYNOTE-006:''' Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. [https://doi.org/10.1056/NEJMoa1503093 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25891173/ PubMed] [https://clinicaltrials.gov/study/NCT01866319 NCT01866319]
+##'''Update:''' Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. [https://doi.org/10.1016/S0140-6736(17)31601-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/28822576/ PubMed]
+##'''PRO analysis:''' Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. [https://doi.org/10.1016/j.ejca.2017.08.032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28987768/ PubMed]
+##'''Update:''' Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. [https://doi.org/10.1016/S1470-2045(19)30388-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345627/ PubMed]
+##'''Update:''' Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. [https://doi.org/10.1200/jco.22.01599 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37348035/ PubMed]
+#'''ECHO-301/KEYNOTE-252:''' Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. [https://doi.org/10.1016/S1470-2045(19)30274-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31221619/ PubMed] [https://clinicaltrials.gov/study/NCT02752074 NCT02752074]
-*[[Pembrolizumab (Keytruda)]] 2 mg/kg IV over 30 minutes once on day 1
+==Temozolomide monotherapy {{#subobject:4e2652|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''21-day cycles'''
+===Regimen {{#subobject:6e73a5|Variant=1}}===
-===Regimen variant #2, 10 mg/kg q2wk {{#subobject:2829cd|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001)]
+|[https://doi.org/10.1200/jco.2000.18.1.158 Middleton et al. 2000b]
-|2011-2012
+|1995-1997
-| style="background-color:#91cf61" |Phase I, >20 pts
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-| style="background-color:#d3d3d3" |
+|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
+|[https://doi.org/10.1200/JCO.2005.01.1551 Kaufmann et al. 2005]
-| rowspan="2" |2013-2014
+|1998-2001
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Ipilimumab_monotherapy_3|Ipilimumab]]
+|[[#Temozolomide_.26_Interferon-alfa_888|Temozolomide & Interferon-alfa]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#fc8d59" |Seems to have inferior ORR
 |-
-|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q3wk
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ Ribas et al. 2013 (A3671009)]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS
+|2006-03 to 2007-07
-|-
+| style="background-color:#1a9851" |Phase 3 (C)
-|}
+|[[#Tremelimumab_monotherapy_999|Tremelimumab]]
-====Immunotherapy====
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
-'''14-day cycles'''
-===Regimen variant #3, 10 mg/kg q3wk {{#subobject:e60ce6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001)]
-|2011-2012
-| style="background-color:#91cf61" |Phase I, >20 pts
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext Ribas et al. 2015 (KEYNOTE-002)]
-| rowspan="2" |2012-2013
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-RT-switch-ooc)
-|Investigator-choice of:<br> 1. [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]<br> 2. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br> 3. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 4. [[#Temozolomide_monotherapy|Temozolomide]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|5. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 2 mg/kg
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
-| rowspan="2" |2013-2014
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|1. [[#Ipilimumab_monotherapy_3|Ipilimumab]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q2wk
-| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS
-|-
-|}
-====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV over 30 minutes once on day 1
-'''21-day cycles'''
-===Regimen variant #4, 200 mg q3wk {{#subobject:e84ce6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30274-8/fulltext Long et al. 2019 (ECHO-301/KEYNOTE-252)]
-|2016-2017
-| style="background-color:#1a9851" |Phase 3 (C)
-|Epacadostat & Pembrolizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS
-|-
-|}
-====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-'''21-day cycle for up to 35 cycles (2 years)'''
-===References===
-#'''Phase 1:''' Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. [https://www.nejm.org/doi/full/10.1056/NEJMoa1305133 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23724846 PubMed] NCT01295827
-##'''Update:''' Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960958-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25034862 PubMed]
-##'''Update:''' Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. [https://jamanetwork.com/journals/jama/fullarticle/2514195 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27092830 PubMed]
-##'''Update:''' Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. [https://doi.org/10.1093/annonc/mdz011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503622/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30715153 PubMed]
-#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26115796 PubMed] NCT01704287
-#'''KEYNOTE-006:''' Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. [https://www.nejm.org/doi/full/10.1056/NEJMoa1503093 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25891173 PubMed] NCT01866319
-##'''Update:''' Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31601-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28822576 PubMed]
-##'''Update:''' Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30388-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345627 PubMed]
-#'''ECHO-301/KEYNOTE-252:''' Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30274-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31221619 PubMed] NCT02752074
-==Temozolomide monotherapy {{#subobject:4e2652|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:6e73a5|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2000.18.1.158 Middleton et al. 2000b]
-|1995-1997
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1200/JCO.2005.01.1551 Kaufmann et al. 2005]
-|1998-2001
-| style="background-color:#1a9851" |Phase 3 (C)
-|Temozolomide & Interferon-alfa
-| style="background-color:#fc8d59" |Seems to have inferior ORR
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ Ribas et al. 2013 (A3671009)]
-|2006-2007
-| style="background-color:#1a9851" |Phase 3 (C)
-|Tremelimumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5, taken while fasting
-'''28-day cycles'''
-===References===
-#Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [https://doi.org/10.1200/jco.2000.18.1.158 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10623706 PubMed]
-#Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. [https://doi.org/10.1200/JCO.2005.01.1551 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16260697 PubMed]
-<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and 25th Annual Meeting of the International Society for Biological Therapy of Cancer, Washington, DC, October 2-4, 2010. -->
-#'''A3671009:''' Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. [https://doi.org/10.1200/JCO.2012.44.6112 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23295794 PubMed] NCT00257205
-=Maintenance immunotherapy for metastatic or unresectable disease=
-==IL-2 monotherapy {{#subobject:fa72a9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Example orders===
-*[[Example orders for IL-2 maintenance biotherapy in melanoma]]
-===Protocol {{#subobject:2ed5d3|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://clincancerres.aacrjournals.org/content/8/9/2775.long O'Day et al. 2002]
-|1998-2000
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Note: timing below is based on the assumption that all cycles begin on a Monday.''
-====Preceding treatment====
-*Induction biochemotherapy
-====Immunotherapy, low-dose cycles (1, 4, 7, 9, 11)====
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 1,000,000 units/m<sup>2</sup> SC once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26
-====Supportive medications====
-*[[Sargramostim (Leukine)]] 125 mcg/m<sup>2</sup> SC once per day on days 1 to 14
-'''28-day cycles, alternating with pulse cycles:'''
-====Immunotherapy, pulse cycles (2, 3, 5, 6, 8, 10, 12)====
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 18,000,000 units/m<sup>2</sup> IV continuous infusion over 6 hours, started on day 1, then 18,000,000 units/m<sup>2</sup> IV continuous infusion over 12 hours, then 18,000,000 units/m<sup>2</sup> IV continuous infusion over 24 hours, then 1,000,000 units/m<sup>2</sup> SC once per day on days 3 to 5, 8 to 12, 15 to 19, 22 to 26
-====Supportive medications====
-*[[Sargramostim (Leukine)]] 125 mcg/m<sup>2</sup> SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)
-*[[Ondansetron (Zofran)]] 32 mg IV or [[Granisetron]] 2 mg IV once per day
-*[[Omeprazole (Prilosec)]] 20 mg PO once every evening
-*[[Acetaminophen (Tylenol)]] 650 mg PO once every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
-*[[Meperidine (Demerol)]] 25 mg IV once every 6 hours as needed for chills and rigors
-'''28-day cycles, alternating with low-dose cycles, for a total of 12 cycles'''
-===References===
-#O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. [http://clincancerres.aacrjournals.org/content/8/9/2775.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12231516 PubMed]
-==Ipilimumab monotherapy {{#subobject:34ee90|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a89958|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1093/annonc/mdq013 O'Day et al. 2010 (CA184-008)]
-|2006-2007
-| style="background-color:#91cf61" |Phase II
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70090-6/abstract Margolin et al. 2012 (CA184-042)]
-|2008-2009
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Preceding treatment====
-*CA184-008 and CA184-042: [[#Ipilimumab_monotherapy_3|Ipilimumab induction]] x 4
-====Immunotherapy====
-*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
-'''12-week cycles'''
-===References===
-#'''CA184-008:''' O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. [https://doi.org/10.1093/annonc/mdq013 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20147741 PubMed] NCT00289627
-#'''CA184-042:''' Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70090-6/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22456429 PubMed] NCT00623766
-==Nivolumab monotherapy {{#subobject:04c9a8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, indefinite {{#subobject:157139|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext Weber et al. 2016 (CheckMate 064)]
-|2013-2014
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*[[#Nivolumab.2C_then_Ipilimumab|Nivolumab, then Ipilimumab induction]] versus [[#Ipilimumab.2C_then_Nivolumab|Ipilimumab, then Nivolumab induction]]
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
-'''14-day cycles'''
-===Regimen variant #2, 2-year course {{#subobject:f7d279|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ Weber et al. 2013 (MCC-15400)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
-|2010-2012
+|2012-11-30 to 2013-11-13
-| style="background-color:#ffffbe" |Phase I
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
+| style="background-color:#d73027" |Inferior PFS
 |-
 |}
-''Note: it is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Preceding treatment====
+====Chemotherapy====
+*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5, taken while fasting
-*[[#Nivolumab_monotherapy_3|Nivolumab induction]]
+'''28-day cycles'''
+</div></div>
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
-'''12-week cycle for 8 cycles (2 years)'''
 ===References===
+#Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [https://doi.org/10.1200/jco.2000.18.1.158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10623706/ PubMed]
-#'''MCC-15400:''' Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. [https://doi.org/10.1200/JCO.2013.51.4802 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24145345 PubMed] NCT01176461
+#Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. [https://doi.org/10.1200/JCO.2005.01.1551 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16260697/ PubMed]
-#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740 PubMed] NCT01783938
+<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and 25th Annual Meeting of the International Society for Biological Therapy of Cancer, Washington, DC, October 2-4, 2010. -->
+#'''A3671009:''' Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. [https://doi.org/10.1200/JCO.2012.44.6112 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23295794/ PubMed] [https://clinicaltrials.gov/study/NCT00257205 NCT00257205]
+#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
+##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
+##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
 [[Category:Melanoma regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Skin cancers]]

Difference between revisions of "Melanoma"

Latest revision as of 17:50, 23 June 2024

Guidelines

ASCO

EDF/EADO/EORTC

ESMO

INMC

NCCN

SITC

Perioperative therapy

Pembrolizumab monotherapy

Eligibility criteria

Neoadjuvant

Immunotherapy

Definitive

Local therapy

Adjuvant

Immunotherapy

References

Neoadjuvant response criteria

Adjuvant therapy

Cisplatin & Temozolomide

Regimen

Preceding treatment

Chemotherapy

References

Ipilimumab monotherapy

Example orders

Regimen variant #1, 3 mg/kg x 1 year

Eligibility criteria

Preceding treatment

Immunotherapy

Regimen variant #2, 10 mg/kg x 1 year

Eligibility criteria

Preceding treatment

Immunotherapy

Regimen variant #3, 3 years

Eligibility criteria

Preceding treatment

Immunotherapy

References

Ipilimumab & Nivolumab

Regimen variant #1

Eligibility criteria

Preceding treatment

Immunotherapy

Regimen variant #2

Eligibility criteria

Preceding treatment

Immunotherapy

References

Nivolumab monotherapy

Regimen variant #1, 240 mg flat dose

Eligibility criteria

Preceding treatment

Immunotherapy

Regimen variant #2, 480 mg flat dose

Eligibility criteria

Preceding treatment

Immunotherapy

Regimen variant #3, weight-based

Eligibility criteria

Preceding treatment

Immunotherapy

References

Pembrolizumab monotherapy

Regimen variant #1, adult dosing

Eligibility criteria

Preceding treatment

Immunotherapy

Regimen variant #2, pediatric dosing

Preceding treatment

Immunotherapy

References

Local therapy

Talimogene laherparepvec monotherapy

Regimen

Local therapy

Subsequent treatment

References

Regimen variant #1, 850 mg/m² q3wk

Regimen variant #2, 850 mg/m² q4wk

Regimen variant #3, 900 mg/m² q3wk

Regimen variant #4, 1000 mg/m² q3wk

Regimen variant #5, 1000 mg/m², split doses, q4wk

Regimen variant #6, 1250 mg/m², split doses, q3wk

Regimen variant #7, 1250 mg/m², split doses, q4wk