Melanoma

Page editor		Section editor
	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:

• BRAF-mutated melanoma
• KIT-mutated melanoma
• NRAS-mutated melanoma
• CNS melanoma
• Uveal melanoma

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 link to PMC article 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article 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)
			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

1. 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 dosing details in manuscript have been reviewed by our editors 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)
			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
			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

1. 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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
3. 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 dosing details in manuscript have been reviewed by our editors 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
4. 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
			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

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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
			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

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. link to original article dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02523313
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03068455
4. 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
5. 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

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 link to PMC article PubMed
3. 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 dosing details in manuscript have been reviewed by our editors 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
4. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03698019
5. 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

1. 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 dosing details in manuscript have been reviewed by our editors 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

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. link to original article dosing details in manuscript have been reviewed by our editors 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 Median OS: 11.3 vs 11.1 mo (HR 0.99, 95% CI 0.85-1.15)

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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00110019
2. 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 dosing details in manuscript have been reviewed by our editors 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

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. link to original article dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors 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	Not reported	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 Median OS: 10.7 vs 12.6 mo (HR 1.14)
Ugurel et al. 2017 (ChemoSensMM)	2008-2012	Phase 3 (C)	Chemosensitivity-directed therapy: 1a. Cisplatin & Paclitaxel 1b. Cytarabine & Treosulfan 1c. Gemcitabine & Treosulfan	Did not meet primary endpoint of OS Median OS: 9 vs 9.2 mo (HR 0.93, 95% CI 0.69-1.25)
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)	Not reported	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed
4. 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 dosing details in manuscript have been reviewed by our editors PubMed
5. 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 dosing details in abstract have been reviewed by our editors PubMed
6. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00518895
7. 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
8. 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 dosing details in manuscript have been reviewed by our editors PubMed
9. 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 dosing details in manuscript have been reviewed by our editors 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
10. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00257205
11. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01359956
12. 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 dosing details in manuscript have been reviewed by our editors 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
13. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00864253
14. 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 dosing details in manuscript have been reviewed by our editors 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

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. link to original article dosing details in manuscript have been reviewed by our editors 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	Not reported	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

1. 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 dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors 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
			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

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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
			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

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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
3. 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 dosing details in abstract have been reviewed by our editors 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
			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 & Nivolumab	Seems to have superior ORR (co-primary endpoint) Did not meet co-primary endpoint of PFS Median PFS: 4.99 vs 4.17 mo (HR 0.92, 97% CI 0.74-1.14)

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

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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
3. 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 dosing details in manuscript have been reviewed by our editors 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
4. 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 dosing details in manuscript have been reviewed by our editors link to PMC article 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

1. 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 dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT03273153
2. 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 dosing details in manuscript have been reviewed by our editors 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

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. link to original article dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

Metastatic or unresectable disease, second-line

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, AUC 2/100

Study	Dates of enrollment	Evidence
Rao et al. 2006	2003-03 to 2005-01	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

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. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. 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
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00111007
4. 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 dosing details in manuscript have been reviewed by our editors 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
5. 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 dosing details in supplement have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors 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

1. 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 to not reported	Phase 2

Immunotherapy

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

14-day cycles

References

1. 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	Not reported 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	Not reported	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

1. 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
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed
4. 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 dosing details in abstract have been reviewed by our editors PubMed NCT00091572
5. 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 dosing details in manuscript have been reviewed by our editors 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
6. 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 dosing details in supplement have been reviewed by our editors 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	Not reported	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

1. 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 dosing details in abstract have been reviewed by our editors 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	Not reported	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

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. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors 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
4. 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 dosing details in manuscript have been reviewed by our editors 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
			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
			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

1. 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
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00289640
3. 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 dosing details in manuscript have been reviewed by our editors 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
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00289627
5. 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 dosing details in abstract have been reviewed by our editors PubMed NCT00623766
6. 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 dosing details in abstract have been reviewed by our editors PubMed NCT01134614
7. 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 dosing details in manuscript have been reviewed by our editors 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
8. 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
9. 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

1. 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 dosing details in manuscript have been reviewed by our editors 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 over 90 minutes once on day 1
• Nivolumab (Opdivo) as follows:
  • Cycle 5 onwards: 3 mg/kg IV over 60 minutes once on day 1

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

References

1. 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 dosing details in manuscript have been reviewed by our editors 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01176461
2. 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 dosing details in manuscript have been reviewed by our editors 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 over 60 minutes once on day 1
  • Cycle 11 onwards: 3 mg/kg IV over 60 minutes once on day 1
• Ipilimumab (Yervoy) as follows:
  • Cycles 7 to 10: 3 mg/kg IV over 90 minutes once on day 1

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

References

1. 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 dosing details in manuscript have been reviewed by our editors 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 Median PFS: 1.9 vs 3.4 mo (HR 1.12, 95% CI 0.93-1.37)
Hamid et al. 2014 (SUMMIT-1)	2009-12 to NR	Phase 3 (C)	Tasisulam	Did not meet primary endpoint of OS Median OS: 9.36 vs 6.77 mo (HR 0.81, 95% CI 0.59-1.12)

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	Not reported	Phase 2

Chemotherapy

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

21-day cycles

References

1. 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 dosing details in abstract have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00522834
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01006252
4. 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 dosing details in manuscript have been reviewed by our editors 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	Not reported	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	Not reported	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

1. 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 dosing details in abstract have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors 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-001melanoma)	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)
			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-001melanoma)	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)
			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-001melanoma)	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)
			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)
			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 endpoint of PFS Median PFS: 4.9 vs 4.7 mo (HR 1.00, 95% CI 0.83-1.20) Did not meet co-primary endpoint of OS Median OS: NYR vs NYR (HR 0.88, 95% CI 0.67-1.16)

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

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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
3. 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 dosing details in manuscript have been reviewed by our editors 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
4. 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 dosing details in abstract have been reviewed by our editors 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 Median OS: 10.7 vs 12.6 mo (HR 1.14)
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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in abstract have been reviewed by our editors PubMed
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