Difference between revisions of "Melanoma"
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|[https://doi.org/10.1097/coc.0b013e3181942a1f Papadopoulos et al. 2009] | |[https://doi.org/10.1097/coc.0b013e3181942a1f Papadopoulos et al. 2009] | ||
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|2003-2005 | |2003-2005 | ||
− | | style="background-color:#91cf61" |Phase | + | | style="background-color:#91cf61" |Phase 1/2 |
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Revision as of 16:33, 28 June 2022
Section editor transclusions
Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: some melanoma regimens can be found on dedicated pages:
39 regimens on this page
75 variants on this page
|
Guidelines
ASCO
- 2020: Seth et al. Systemic Therapy for Melanoma: ASCO Guideline
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
- 2020: Michielin et al. ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee
Older
- 2019: Michielin et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
- 2015: Dummer et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. PubMed
INMC
- 2019: Amaria et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium
NCCN
Neoadjuvant response criteria
- 2018: Tetzlaff et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma
Adjuvant therapy
Cisplatin & Temozolomide
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lian et al. 2013 | 2007-2009 | Randomized Phase 2 (C) | 1. Interferon alfa-2b | Superior RFS |
2. Observation | Superior OS |
Preceding treatment
Chemotherapy
- Cisplatin (Platinol) 25 mg/m2 IV once per day on days 1 to 3
- Temozolomide (Temodar) 200 mg/m2/day PO on days 1 to 5
21-day cycle for 6 cycles
References
- Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. link to original article contains verified protocol PubMed ChiCTR-TRC-11001798
Ipilimumab monotherapy
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Example orders
Regimen variant #1, 3 mg/kg x 1 year
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tarhini et al. 2019 (ECOG E1609) | 2011-2014 | Phase 3 (E-switch-ic) | Interferon alfa-2b | Seems to have superior OS |
Ipilimumab; 10 mg/kg | Not reported |
Preceding treatment
- Complete resection of stage IIIB, IIIC, or IV melanoma
Immunotherapy
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
3-week cycle for 4 cycles, then 12-week cycle for up to 4 cycles
Regimen variant #2, 10 mg/kg x 1 year
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | 12-month recurrence-free survival (RFS) | Comparator RFS |
---|---|---|---|---|---|---|
Tarhini et al. 2019 (ECOG E1609) | 2011-2014 | Phase 3 (E-switch-ic) | Interferon alfa-2b | Did not meet primary endpoint of OS | ||
Ipilimumab; 3 mg/kg | Not reported | |||||
Weber et al. 2017 (CheckMate 238) | 2015 | Phase 3 (C) | Nivolumab | Inferior RFS | 61% overall Stage IIIB or IIIC: 62% (95% CI: 56-66.5) Stage IV: 57.5% (95% CI: 46-67) |
70.5% overall Stage IIIB or IIIC: 72% (95% CI, 67-77) Stage IV: 63% (95% CI, 52-72.5) |
Preceding treatment
- Complete resection of stage IIIB, IIIC, or IV melanoma
Immunotherapy
- Ipilimumab (Yervoy) 10 mg/kg IV once on day 1
3-week cycle for 4 cycles, then 12-week cycle for up to 4 cycles
Regimen variant #3, 3 years
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Eggermont et al. 2015 (EORTC 18071) | 2008-2011 | Phase 3 (E-RT-esc) | Placebo | Superior OS1 (HR 0.73, 95% CI 0.60-0.89) |
Similar HRQoL2 |
1Reported efficacy is based on the 2019 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 clinically relevance.
Preceding treatment
- Complete resection of stage III cutaneous melanoma
Immunotherapy
- Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1
21-day cycle for 4 cycles, then 12-week cycle for 12 cycles (3 years)
References
- EORTC 18071: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Karra Gurunath R, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. link to original article contains verified protocol PubMed NCT00636168
- Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
- HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to original article link to PMC article PubMed
- Update: Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. link to original article PubMed
- CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed NCT02388906
- Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
- ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains verified protocol PubMed NCT01274338
- SWOG S1404: NCT02506153
Ipilimumab & Nivolumab
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Regimen
Study | Years 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 Median RFS: Not reached vs 6.4 mo (HR 0.23, 97.5% CI 0.12-0.45) |
Preceding treatment
- Resection or radiotherapy of stage IV melanoma, 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)
References
- IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains verified protocol PubMed NCT02523313
Nivolumab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | 12-month recurrence-free survival (RFS) | Comparator RFS |
---|---|---|---|---|---|---|
Weber et al. 2017 (CheckMate 238) | 2015 | Phase 3 (E-RT-switch-ic) | Ipilimumab | Superior RFS RFS12: 70.5% vs 60.8% (HR 0.65, 97.56% CI 0.51-0.83) |
71% overall Stage IIIB or IIIC: 72.3% (95% CI, 67 to 77) Stage IV: 63.0% (95% CI, 52 to 73) |
61% overall Stage IIIB or IIIC: 61.6% (95% CI, 56 to 66.5) Stage IV: 57.5% (95% CI, 46 to 67) |
Zimmer et al. 2020 (IMMUNED) | 2015-2018 | Randomized Phase 2 (E-esc) | 1. Ipilimumab & Nivolumab | Not reported | ||
2. Placebo | Superior RFS Median RFS: 12.4 vs 6.4 mo (HR 0.56, 97.5% CI 0.33-0.94) |
52% (95% CI, 38 to 64) |
Preceding treatment
- CheckMate 238: Complete resection of stage IIIB, IIIC, or IV melanoma
- IMMUNED: Resection or radiotherapy of stage IV melanoma, with NED
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycle for up to 26 cycles (1 year)
References
- CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed NCT02388906
- Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
- IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains verified protocol PubMed NCT02523313
- PIVOT-12: NCT04410445
Pembrolizumab monotherapy
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FDA-recommended dose |
Regimen variant #1, adult dosing
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Eggermont et al. 2018 (KEYNOTE-054) | 2015-2016 | Phase 3 (E-RT-esc) | Placebo | Superior RFS1 RFS42: 60% vs 41% (HR 0.59, 99% CI 0.49-0.70) |
Grossmann et al. 2022 (SWOG S1404) | 2015-2017 | Phase 3 (E-switch-ic) | 1. HD-Interferon alfa-2b 2. Ipilimumab |
Superior RFS (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 Median RFS: NYR vs NYR (HR 0.61, 95% CI 0.45-0.82) |
1Reported efficacy is based on the 2021 update.
2Reported efficacy is from the second interim analysis.
Preceding treatment
- 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Luke et al. 2022 (KEYNOTE-716) | 2018-2020 | Phase 3 (E-RT-esc) | Placebo | Superior RFS1 Median RFS: NYR vs NYR (HR 0.61, 95% CI 0.45-0.82) |
1Reported efficacy is from the second interim analysis.
Preceding treatment
- Complete regional lymphadenectomy, within 13 weeks
Immunotherapy
- Pembrolizumab (Keytruda) 2 mg/kg (maximum dose of 200 mg) IV once on day 1
21-day cycle for 18 cycles (1 year)
References
- KEYNOTE-054: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains verified protocol PubMed NCT02362594
- Update: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. Epub 2020 Sep 18. link to original article link to PMC article PubMed
- Update: Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Apr 12:S1470-2045(21)00065-6. Epub ahead of print. link to original article PubMed
- HRQoL analysis: Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Apr 12:S1470-2045(21)00081-4. Epub ahead of print. link to original article PubMed
- KEYNOTE-716: Luke JJ, RUtkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, Merino L, Khattak M, Schadendorf D, Long GV, Ascierto PA, Mandala M, Galitiis F, Haydon A, Dummer R Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer PA, Kirkwood JM, Chen K, Diedi SJ, Ahsan S, Ibrahim N, Eggermont AMM. Lancet. 2022 Apr 30;399(10336):1718-1729. Epub 2022 Mar 31. link to original article NCT03553836
- SWOG S1404: Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. link to original article contains verified protocol link to PMC article PubMed NCT02506153
Local therapy
Talimogene laherparepvec monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Andtbacka et al. 2015 (OPTiM) | 2009-2011 | Phase 3 (E-RT-switch-ooc) | GM-CSF | Seems to have superior OS1 (HR 0.79, 95% CI 0.62-1.00) |
1Reported efficacy is based on the 2019 update.
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.
Immunotherapy
- 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 cycle for 1 cycle, then 14-day cycle for at least 12 cycles
Subsequent treatment
- Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months
References
- OPTiM: Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. link to original article contains verified protocol PubMed NCT00769704
- Update: Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. link to original article link to PMC article PubMed
Metastatic or unresectable disease, first-line
ABC
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ABC: Abraxane (Paclitaxel nanoparticle albumin-bound), Bevacizumab, Carboplatin
Regimen
Study | Years 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 |
The doses listed here are the amended starting doses.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 80 mg/m2 IV once per day on days 1, 8, 15
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- N0775: Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. link to original article contains verified protocol link to PMC article PubMed NCT00626405
Carboplatin & Paclitaxel (CP)
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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
Regimen variant #1, 5/175
Study | Years 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Flaherty et al. 2013 (ECOG E2603) | 2005-2008 | Phase 3 (C) | CP & Sorafenib | Did not meet primary endpoint of OS |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
- Cycle 5 onwards: 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 onwards: 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for up to 10 cycles
References
- ECOG E2603: Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. link to original article contains verified protocol link to PMC article PubMed NCT00110019
- BCH-MM-131101: Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. link to original article contains verified protocol PubMed NCT02023710
Carboplatin & Paclitaxel (CP) & Bevacizumab
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CPB: Carboplatin, Paclitaxel, Bevacizumab
Regimen
Study | Years 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 Median OS: 14 vs 9 mo (HR 0.61, 95% CI 0.41-0.92) |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- BCH-MM-131101: Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. link to original article contains verified protocol PubMed NCT02023710
Carboplatin & nab-Paclitaxel
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Regimen
Study | Years 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 medications
- "All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
References
- N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. link to original article contains verified protocol link to PMC article PubMed NCT00404235
Cisplatin & Dacarbazine
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Regimen
Study | Years 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 prior to becoming a standard comparator arm.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
21-day cycle for 6 cycles
References
- Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains verified protocol PubMed
Cisplatin, Dacarbazine, Paclitaxel
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Papadopoulos et al. 2009 | NR in abstract | Phase 1/2 |
Note: cycle length is not specified in the abstract. This is the suggested phase II dosing.
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 120 mg/m2 IV once per day on days 1 & 8
Continued indefinitely
References
- Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. link to original article contains protocol PubMed
Dacarbazine monotherapy
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Example orders
Regimen variant #1, 850 mg/m2 q3wk
Study | Years 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 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 | Years 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 prior to becoming a standard comparator arm.
Chemotherapy
- Dacarbazine (DTIC) 850 mg/m2 IV once on day 1
28-day cycles
Regimen variant #3, 1000 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
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) |
Robert et al. 2014 (CheckMate 066) | 2013-2014 | Phase 3 (C) | Nivolumab | Inferior OS |
Chemotherapy
- Dacarbazine (DTIC) 1000 mg/m2 IV once on day 1
21-day cycles
References
- Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. link to original article contains protocol PubMed
- AGENDA: Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. Epub 2006 Sep 11. link to original article contains verified protocol PubMed NCT00518895
- CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed NCT00324155
- Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
- CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains verified protocol PubMed NCT01721772
- Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
- Update: Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. link to original article link to PMC article PubMed
Dacarbazine & Ipilimumab
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (CA184-024) | 2006-2008 | Phase 3 (E-esc) | Dacarbazine | Superior OS |
Chemotherapy
- Dacarbazine (DTIC) as follows:
- Cycles 1 to 8: 850 mg/m2 IV once on day 1
Immunotherapy
- Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 10 mg/kg IV once on day 1
- Cycle 9 onwards: 10 mg/kg IV once on day 1
21-day cycle for 8 cycles, then 12-week cycles
References
- CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed NCT00324155
- Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
Ipilimumab monotherapy
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Example orders
Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Larkin et al. 2015 (CheckMate 067) | 2013-2014 | Phase 3 (C) | 1. Ipilimumab & Nivolumab | Inferior OS1 | Equivalent HRQoL |
2. Nivolumab | Inferior OS1 | Equivalent HRQoL | |||
Postow et al. 2015 (CheckMate 069) | 2013-2014 | Phase 3 (C) | Ipilimumab & Nivolumab | Inferior PFS |
1Reported efficacy for CheckMate 067 is based on the 2021 update.
Immunotherapy
- Ipilimumab (Yervoy) 3 mg/kg IV over 90 minutes once on day 1
21-day cycle for 4 cycles
References
- CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article contains verified protocol PubMed NCT01927419
- Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
- CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed NCT01844505
- HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
- Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
- Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
- Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. link to original article link to PMC article PubMed
Ipilimumab & Nivolumab
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Regimen variant #1
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Larkin et al. 2015 (CheckMate 067) | 2013-2014 | Phase 3 (E-RT-esc) | 1. Ipilimumab | Superior OS1 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 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.
Notably, on 9/13/16 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Postow et al. 2015 (CheckMate 069) | 2013-2014 | Phase 3 (E-esc) | Ipilimumab | Superior PFS |
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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Lebbé et al. 2019 (CheckMate 511) | 2016-2017 | 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Lebbé et al. 2019 (CheckMate 511) | 2016-2017 | Phase 3b/4 (E-switch-ic) | Ipilimumab & Nivolumab; NIVO1+IPI3 | Not evaluated | Fewer grade 3 to 5 TRAEs |
Immunotherapy
- Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 1 mg/kg IV once on day 1
- Nivolumab (Opdivo) as follows:
- Cycles 1 to 4: 3 mg/kg IV once on day 1
- Cycle 5 onwards: 480 mg IV once on day 1
21-day cycle for 4 cycles, then 28-day cycles
References
- CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article contains verified protocol PubMed NCT01927419
- Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
- CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed NCT01844505
- HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
- Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
- Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
- Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24.link to original article link to PMC article PubMed
- CheckMate 511: Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. Epub 2019 Feb 27. link to original article link to PMC article contains protocol PubMed NCT02714218
Nivolumab monotherapy
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Regimen variant #1, weight-based
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Robert et al. 2014 (CheckMate 066) | 2013-2014 | Phase 3 (E-RT-switch-ooc) | Dacarbazine | Superior OS1 5-year OS: 39% vs 17% (HR 0.50, 95% CI 0.40-0.63) |
|
Larkin et al. 2015 (CheckMate 067) | 2013-2014 | Phase 3 (E-switch-ic) | 1. Ipilimumab | Superior OS2 Median OS: 36.9 vs 19.9 mo (HR 0.53, 95% CI 0.44-0.64) |
Equivalent HRQoL |
2. Ipilimumab & Nivolumab | Inferior PFS | Equivalent HRQoL |
1Reported efficacy for CheckMate 066 is based on the 2020 update.
2Reported efficacy for CheckMate 067 is based on the 2021 update.
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
Regimen variant #2, flat dosing
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tawbi et al. 2022 (RELATIVITY-047) | 2018-2020 | Phase 2/3 (C) | Nivolumab & Relatlimab | Inferior PFS |
Immunotherapy
- Nivolumab (Opdivo) 480 mg IV once on day 1
28-day cycles
References
- CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains verified protocol PubMed NCT01721772
- Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
- Update: Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. link to original article link to PMC article PubMed
- CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed NCT01844505
- HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
- Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
- Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
- Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. link to original article link to PMC article PubMed
- RELATIVITY-047: Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. link to original article contains verified protocol PubMed NCT03470922
- PIVOT IO 001: NCT03635983
Nivolumab & Relatlimab
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tawbi et al. 2022 (RELATIVITY-047) | 2018-2020 | Phase 2/3 (E-RT-esc) | Nivolumab | Superior PFS Median PFS: 10.1 vs 4.6 mo (HR 0.75, 95% CI 0.62-0.92) |
Immunotherapy
- Nivolumab and relatlimab (Opdualag) 480/160 mg IV once on day 1
28-day cycles
References
- RELATIVITY-047: Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. link to original article contains verified protocol PubMed NCT03470922
- Update: Long GV, Hodi S, Lipson EJ, Schadenodorf D, Ascierto PAA, Matamala L, Salman P, Gutierrez EC, Rutkowski P, Gogas H, Lao CD, De Menezes JJ, Dalle S, Arance AM, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. J Clin Oncol 40, 2022 (suppl 36; abstr 360385). link to abstract
Pembrolizumab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gogas et al. 2020 (IMspire170) | 2017-2019 | Phase 3 (C) | Cobimetinib & Atezolizumab | Did not meet primary endpoint of PFS |
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycles
References
- IMspire170: Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Francesco Ferrucci P, Pigozzo J, Rutkowski P, Mackiewicz J, Rooney I, Voulgari A, Troutman S, Pitcher B, Guo Y, Yan Y, Castro M, Mulla S, Flaherty K, Arance A. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021 Mar;32(3):384-394. Epub 2020 Dec 10. link to original article contains verified protocol PubMed NCT03273153
- KEYNOTE-034: NCT02263508
Temozolomide & Bevacizumab
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TB: Temozolomide & Bevacizumab
Regimen
Study | Years 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 |
Chemotherapy
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- N0775: Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. link to original article contains verified protocol link to PMC article PubMed NCT00626405
Metastatic or unresectable disease, second-line
Carboplatin & Paclitaxel (CP)
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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin
Regimen variant #1, AUC 2/100
Study | Evidence |
---|---|
Rao et al. 2006 | Retrospective |
Chemotherapy
- Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, AUC 6/175
Study | Years 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.
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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hauschild et al. 2009 (Bayer 11718) | 2005-2006 | 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 |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
- Cycle 5 onwards: 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 onwards: 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 | Years 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 is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
Chemotherapy
- Carboplatin (Paraplatin) 200 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
References
- Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. link to original article contains protocol PubMed
- Retrospective: Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article PubMed
- Bayer 11718: Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. link to original article contains verified protocol PubMed NCT00111007
- CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article contains protocol PubMed NCT01721746
- Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed
Carboplatin & nab-Paclitaxel
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Regimen
Study | Years 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 medications
- "All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
References
- N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. link to original article contains verified protocol link to PMC article PubMed NCT00404235
TILs
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TILs: Tumor Ifiltrating Lymphocytes
Regimen
Study | Evidence |
---|---|
Sarnaik et al. 2021 (C-144-01) | Phase 2 |
Preceding treatment
- FC lymphodepletion
Immunotherapy
- Lifileuecel (LN-144) administered 24 hours from last dose of fludarabine
- IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV over 15 minutes every 8-12 hours as tolerated for up to 6 doses starting 3-24 hours after completing lifileucel infusion
References
- C-144-01: Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. Epub 2021 May 12. Erratum in: J Clin Oncol. 2021 Sep 10;39(26):2972. link to original article link to PMC article PubMed NCT02360579
Metastatic or unresectable disease
Note: these regimens have not yet been classified by line of treatment.
CVD (Vindesine)
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CVD: Cisplatin, Vindesine, Dacarbazine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jungnelius et al. 1998 | NR | Phase 3 (E-esc) | Dacarbazine & Vindesine | Superior TTP |
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
References
- Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. link to original article PubMed
- Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. link to original article PubMed
Dacarbazine monotherapy
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Example orders
Regimen variant #1, 850 mg/m2 q3wk
Study | Years of enrollment | Evidence |
---|---|---|
Pritchard et al. 1980 | NR in abstract | Phase 2 |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT 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 #3, 900 mg/m2 q3wk
Study | Years 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 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chapman et al. 1999 | 1991-1997 | Phase 3 (C) | Dartmouth regimen | Might have inferior ORR |
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 |
Patel et al. 2011 (EORTC 18032) | 2004-2007 | Phase 3 (C) | Temozolomide | Did not meet primary endpoint of OS |
Ribas et al. 2013 (A3671009) | 2006-2007 | Phase 3 (C) | Tremelimumab | Did not meet primary endpoint of OS |
Ugurel et al. 2017 (ChemoSensMM) | 2008-2012 | Phase 3 (C) | Chemosensitivity-directed therapy | Did not meet primary endpoint of OS |
Hersh et al. 2015 (CA033) | 2009-2011 | Phase 3 (C) | nab-Paclitaxel | Seems to have 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.
Chemotherapy
- Dacarbazine (DTIC) 1000 mg/m2 IV once on day 1
21-day cycles
Regimen variant #5, 1000 mg/m2, split doses, q4wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Falkson et al. 2003 (ECOG E3690) | NR | Phase 3 (C) | 1. DTIC & Interferon 2. DTIC & Tamoxifen 3. DTIC, Interferon, Tamoxifen |
Seems to have inferior ORR |
Chemotherapy
- Dacarbazine (DTIC) 200 mg/m2 IV once per day on days 1 to 5
28-day cycles
Regimen variant #6, 1250 mg/m2, split doses, q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cocconi et al. 1992 | 1983-1988 | Phase 3 (C) | Dacarbazine & Tamoxifen | Seems to have inferior OS |
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 | Years 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
Regimen variant #8, 2500 mg/m2, split doses, q4wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Luikart et al. 1984 | NR | Phase 3 (C) | BVP | Did not meet efficacy endpoints |
Chemotherapy
- Dacarbazine (DTIC) 250 mg/m2 IV once per day on days 1 to 10
28-day cycles
References
- Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
- Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article contains verified protocol PubMed
- Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains verified protocol PubMed
- ECOG E3690: Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; ECOG. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. link to original article contains verified protocol PubMed
- Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. link to original article contains protocol PubMed
- Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
- Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains verified protocol PubMed
- C-100-21: Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. link to original article does not contain protocol PubMed
- Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. link to original article link to PMC article contains protocol PubMed
- EORTC 18032: Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; EORTC Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. link to original article contains protocol PubMed NCT00091572
- A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains verified protocol link to PMC article PubMed NCT00257205
- SICOG 0109: Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. link to original article link to PMC article contains verified protocol PubMed NCT01359956
- CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed NCT01721746
- Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed
- CA033: Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains verified protocol link to PMC article PubMed NCT00864253
- ChemoSensMM: Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. [=18635 link to original article] link to PMC article contains verified protocol PubMed NCT00779714
Docetaxel monotherapy
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Aamdal et al. 1994 | NR in abstract | Phase 2 |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
Supportive medications
- "No prophylactic treatment with steroids or antihistamines was given."
21-day cycles
References
- Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J; EORTC Early Clinical Trials Group. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. link to original article contains protocol PubMed
Fotemustine monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Avril et al. 2004 | 1998-2000 | Phase 3 (E-switch-ic) | Dacarbazine | Seems to have superior ORR |
Chemotherapy
- Fotemustine (Muphoran) as follows:
- Weeks 1 to 3: 100 mg/m2 IV once per day on days 1, 8, 15
- Weeks 4 to 8: no treatment
- Week 9 onwards: 100 mg/m2 IV once on day 1, every 3 weeks
8-week induction cycle, then 21-day cycles
References
- Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains verified protocol PubMed
High-dose Interleukin-2
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HD IL-2: High-Dose InterLeukin-2
Example orders
Regimen variant #1, 600k, up to 3 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 1993 | NR | Phase 3 (C) | HD IL-2 & IFN alfa-2a | Did not meet primary endpoint of OS50% |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT 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 medications
- Included:
- Acetaminophen (Tylenol)
- Indomethacin (Indocin)
- Meperidine (Demerol)
- Ranitidine (Zantac)
- Cimetidine (Tagamet)
- Hydroxyzine (Atarax)
- Diphenhydramine (Benadryl)
- Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
12-week cycle for up to 3 cycles
Regimen variant #2, 600k, up to 5 cycles
Study | Years 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 medications
- Included:
- Acetaminophen (Tylenol)
- Indomethacin (Indocin)
- Meperidine (Demerol)
- Ranitidine (Zantac)
- Cimetidine (Tagamet)
- Hydroxyzine (Atarax)
- Diphenhydramine (Benadryl)
- Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
6- to 12-week cycle for up to 5 cycles
Regimen variant #3, 720k, up to 3 cycles
Study | Years 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 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 medications
- Included:
- Acetaminophen (Tylenol)
- Indomethacin (Indocin)
- Meperidine (Demerol)
- Ranitidine (Zantac)
- Cimetidine (Tagamet)
- Hydroxyzine (Atarax)
- Diphenhydramine (Benadryl)
- Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
2-month cycle for up to 3 cycles
Regimen variant #4, 720k, up to 5 cycles
Study | Years 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 medications
- Included:
- Acetaminophen (Tylenol)
- Indomethacin (Indocin)
- Meperidine (Demerol)
- Ranitidine (Zantac)
- Cimetidine (Tagamet)
- Hydroxyzine (Atarax)
- Diphenhydramine (Benadryl)
- Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
6- to 12-week cycle for up to 5 cycles
Regimen variant #5, 720k, indefinite
Study | Years 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 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 medications
- Included:
- Acetaminophen (Tylenol)
- Indomethacin (Indocin)
- Meperidine (Demerol)
- Ranitidine (Zantac)
- Cimetidine (Tagamet)
- Hydroxyzine (Atarax)
- Diphenhydramine (Benadryl)
- Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
7-week cycles
References
- Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. link to original article contains verified protocol PubMed
- Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article contains verified protocol PubMed
- Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. link to original article contains verified protocol PubMed
- Update: Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. PubMed
- NCI-2012-02897: Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011 Jun 2;364(22):2119-27. link to original article link to PMC article contains verified protocol PubMed NCT00019682
Ipilimumab monotherapy
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Example orders
Regimen variant #1, 3 mg/kg
FDA-recommended dose |
Study | Years 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 | |||
Ascierto et al. 2017 (CA184-169) | 2012 | Phase 3 (C) | Ipilimumab; 10 mg/kg | Seems to have inferior OS |
Robert et al. 2015 (KEYNOTE-006) | 2013-2014 | Phase 3 (C) | 1. Pembrolizumab; 10 mg/kg q2wks | Inferior OS |
2. Pembrolizumab; 10 mg/kg q3wks | Inferior OS |
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
Study | Years 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 | ||
O'Day et al. 2010 (CA184-008) | 2006-2007 | Phase 2 | ||
Margolin et al. 2012 (CA184-042) | 2008-2009 | 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 | Phase 3 (E-esc) | Ipilimumab; 3 mg/kg | Seems to have superior OS1 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
Subsequent treatment
- CA184-008 & CA184-042: Patients who were clinically stable could proceed to ipilimumab maintenance
References
- Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. link to original article PubMed
- CA184-022: Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. link to original article contains verified protocol PubMed NCT00289640
- MDX010-20: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains verified protocol link to PMC article PubMed NCT00094653
- Update: McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. link to original article PubMed
- CA184-008: O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains verified protocol PubMed NCT00289627
- CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains protocol PubMed NCT00623766
- ECOG E1608: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. link to original article link to PMC article contains protocol PubMed NCT01134614
- KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains verified protocol PubMed NCT01866319
- Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
- Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
- CA184-169: Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. link to original article PubMed NCT01515189
- 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
Ipilimumab & Nivolumab
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Regimen variant #1
Study | Years of enrollment | Evidence |
---|---|---|
Wolchok et al. 2013 (CheckMate 004) | 2009-2013 | Phase 1 |
These doses were from the cohort deemed by CheckMate 004 as being "the maximum doses that were associated with an acceptable level of adverse events."
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
References
- Phase I: Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. link to original article contains verified protocol link to supplementary appendix link to PMC article PubMed NCT01024231
Ipilimumab, then Nivolumab
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Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Weber et al. 2016 (CheckMate 064) | 2013-2014 | Randomized Phase 2 (E-switch-ic) | Nivolumab, then Ipilimumab | Seems to have inferior OS |
Immunotherapy, part 1
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 6 cycles
Subsequent treatment
References
- CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains protocol link to PMC article PubMed NCT01783938
Nivolumab monotherapy
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Regimen variant #1, limited duration
Study | Years of enrollment | Evidence |
---|---|---|
Weber et al. 2013 (MCC-15400) | 2010-2012 | Phase I |
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 12 cycles
Subsequent treatment
Regimen variant #2, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Weber et al. 2015 (CheckMate 037) | 2012-2014 | Phase 3 (E-RT-switch-ooc) | 1. Dacarbazine 2. Carboplatin & Paclitaxel |
Superior ORR |
Note: CheckMate 037 did not meet the co-primary endpoint of OS.
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
References
- MCC-15400: Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. link to original article contains verified protocol link to PMC article PubMed NCT01176461
- CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed NCT01721746
- 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 PubMed
Nivolumab, then Ipilimumab
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Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Weber et al. 2016 (CheckMate 064) | 2013-2014 | Randomized Phase 2 (E-switch-ic) | Ipilimumab, then Nivolumab | Seems to have superior OS |
Immunotherapy, part 1
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 6 cycles, followed by:
Immunotherapy, part 2
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
References
- CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains protocol link to PMC article PubMed NCT01783938
Paclitaxel monotherapy
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Example orders
Regimen variant #1, 80 mg/m2, 3 out of 4 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Day et al. 2013 (SYMMETRY) | 2007-2009 | Phase 3 (C) | Elesclomol & Paclitaxel | Did not meet primary endpoint of PFS |
Hamid et al. 2014 (SUMMIT-1) | 2009-NR | Phase 3 (C) | Tasisulam | Did not meet primary endpoint of OS |
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, 250 mg/m2 q3wk
Study | Years of enrollment | Evidence |
---|---|---|
Legha et al. 1990 | NR | Phase 2 |
Chemotherapy
- Paclitaxel (Taxol) 250 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
References
- Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. link to original article contains protocol PubMed
- SYMMETRY: O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. link to original article contains verified protocol PubMed NCT00522834
- SUMMIT-1: Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. link to original article contains verified protocol PubMed NCT01006252
nab-Paclitaxel monotherapy
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Regimen variant #1
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hersh et al. 2012 | NR | Phase 2 | ||
Hersh et al. 2015 (CA033) | 2009-2011 | Phase 3 (E-switch-ic) | Dacarbazine | Seems to have superior PFS |
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 | Years of enrollment | Evidence |
---|---|---|
Hersh et al. 2012 | NR | Phase 2 |
Note: this dose was intended for previously treated patients.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. link to original article contains protocol PubMed
- CA033: Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains verified protocol link to PMC article PubMed NCT00864253
Pembrolizumab monotherapy
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Regimen variant #1, 2 mg/kg q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hamid et al. 2013 (KEYNOTE-001) | 2011-2012 | Phase I, >20 pts | ||
Ribas et al. 2015 (KEYNOTE-002) | 2012-2013 | Randomized Phase 2 (E-RT-switch-ooc) | Investigator-choice of: 1. Carboplatin & Paclitaxel 2. Dacarbazine 3. Paclitaxel 4. Temozolomide |
Superior PFS |
5. Pembrolizumab; 10 mg/kg q3wk | Did not meet primary endpoint of PFS |
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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hamid et al. 2013 (KEYNOTE-001) | 2011-2012 | Phase I, >20 pts | ||
Robert et al. 2015 (KEYNOTE-006) | 2013-2014 | Phase 3 (E-RT-switch-ic) | 1. Ipilimumab | Superior OS |
2. Pembrolizumab; 10 mg/kg q3wk | Did not meet primary endpoints of PFS/OS |
Immunotherapy
- Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1
14-day cycles
Regimen variant #3, 10 mg/kg q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hamid et al. 2013 (KEYNOTE-001) | 2011-2012 | Phase I, >20 pts | ||
Ribas et al. 2015 (KEYNOTE-002) | 2012-2013 | Randomized Phase 2 (E-RT-switch-ooc) | Investigator-choice of: 1. Carboplatin & Paclitaxel 2. Dacarbazine 3. Paclitaxel 4. Temozolomide |
Superior PFS |
5. Pembrolizumab; 2 mg/kg | Did not meet primary endpoint of PFS | |||
Robert et al. 2015 (KEYNOTE-006) | 2013-2014 | Phase 3 (E-RT-switch-ic) | 1. Ipilimumab | Superior OS |
2. Pembrolizumab; 10 mg/kg q2wk | Did not meet primary endpoints of PFS/OS |
Immunotherapy
- Pembrolizumab (Keytruda) 10 mg/kg IV over 30 minutes once on day 1
21-day cycles
Regimen variant #4, 200 mg q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Long et al. 2019 (ECHO-301/KEYNOTE-252) | 2016-2017 | Phase 3 (C) | Epacadostat & Pembrolizumab | Did not meet primary endpoints of PFS/OS |
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
References
- Phase 1: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. link to original article link to PMC article PubMed NCT01295827
- Update: Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
- Update: Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. link to original article PubMed
- Update: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. link to original article link to PMC article PubMed
- KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains verified protocol PubMed NCT01704287
- KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains verified protocol PubMed NCT01866319
- Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
- Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
- ECHO-301/KEYNOTE-252: Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. link to original article contains protocol PubMed NCT02752074
Temozolomide monotherapy
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Regimen
Study | Years 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) | 2006-2007 | Phase 3 (C) | Tremelimumab | Did not meet primary endpoint of OS |
Chemotherapy
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5, taken while fasting
28-day cycles
References
- Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
- Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. link to original article contains protocol PubMed
- A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains verified protocol link to PMC article PubMed NCT00257205
Maintenance immunotherapy for metastatic or unresectable disease
IL-2 monotherapy
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Example orders
Protocol
Study | Years 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 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
Supportive medications
- Sargramostim (Leukine) 125 mcg/m2 SC once per day on days 1 to 14
28-day cycles, alternating with pulse cycles:
Immunotherapy, pulse cycles (2, 3, 5, 6, 8, 10, 12)
- 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
Supportive medications
- 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)
- Ondansetron (Zofran) 32 mg IV or Granisetron 2 mg IV once per day
- Omeprazole (Prilosec) 20 mg PO once every evening
- Acetaminophen (Tylenol) 650 mg PO once every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
- Meperidine (Demerol) 25 mg IV once every 6 hours as needed for chills and rigors
28-day cycles, alternating with low-dose cycles, for a total of 12 cycles
References
- O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. link to original article contains verified protocol PubMed
Ipilimumab monotherapy
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
O'Day et al. 2010 (CA184-008) | 2006-2007 | Phase 2 |
Margolin et al. 2012 (CA184-042) | 2008-2009 | Phase 2 |
Preceding treatment
- CA184-008 and CA184-042: Ipilimumab induction x 4
Immunotherapy
- Ipilimumab (Yervoy) 10 mg/kg IV once on day 1
12-week cycles
References
- CA184-008: O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains verified protocol PubMed NCT00289627
- CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains protocol PubMed NCT00623766
Nivolumab monotherapy
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Regimen variant #1, indefinite
Study | Years of enrollment | Evidence |
---|---|---|
Weber et al. 2016 (CheckMate 064) | 2013-2014 | Non-randomized portion of RCT |
Preceding treatment
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
Regimen variant #2, 2-year course
Study | Years of enrollment | Evidence |
---|---|---|
Weber et al. 2013 (MCC-15400) | 2010-2012 | Phase I |
Note: it is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.
Preceding treatment
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
12-week cycle for 8 cycles (2 years)
References
- 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. link to original article contains verified protocol link to PMC article PubMed NCT01176461
- CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains protocol link to PMC article PubMed NCT01783938