Difference between revisions of "Melanoma"

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===References===
 
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# '''EORTC 1325:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. [https://www.nejm.org/doi/10.1056/NEJMoa1802357 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29658430 PubMed]
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# '''EORTC 1325/KEYNOTE-054:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. [https://www.nejm.org/doi/10.1056/NEJMoa1802357 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29658430 PubMed]
  
 
==Placebo==
 
==Placebo==

Revision as of 02:14, 18 May 2019

Section editor
Bethbuchbinder.jpg
 Elizabeth Buchbinder, MD
Dana-Farber Cancer Institute
Boston, MA
LinkedIn

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. 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

EDF/EADO/EORTC

ESMO

NCCN

Adjuvant therapy

CVD, IL-2, IFN alfa-2b - sequential biochemotherapy

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CVD, IL-2, IFN alfa-2b: Cisplatin, Vinblastine, Dacarbazine, high-dose InterLeukin-2, InterFeroN alfa-2b
bioCT: bioChemoTherapy

Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Flaherty et al. 2014 (SWOG S0008) Phase III (E) IFN alfa-2b Seems to have superior RFS

Preceding treatment

Chemoimmunotherapy

21-day cycle for 3 cycles

References

  1. SWOG S0008: Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK. Southwest Oncology Group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of Cancer and Leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8. Epub 2014 Oct 20. link to original article link to PMC article contains verified protocol PubMed

Interferon alfa-2a monotherapy

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Variant #1, 12 months

Study Evidence Comparator Comparative Efficacy
Pehamberger et al. 1998 Phase III (E) Observation Seems to have superior DFS

Preceding treatment

Immunotherapy

  • Interferon alfa-2a (Roferon-A) as follows:
    • Weeks 1 to 3: 3,000,000 international units SC once per day (21 doses total)
    • Weeks 4 to 52: 3,000,000 international units SC three times per week

12-month course

Variant #2, 18 months

Study Evidence Comparator Comparative Efficacy
Grob et al. 1998 Phase III (E) Observation Might have superior OS
Hauschild et al. 2010 Phase III (C) IFN alfa-2a x 5 y Seems not superior

Preceding treatment

Immunotherapy

18-month course

Variant #3, 24 months

Study Evidence Comparator Efficacy Toxicity
Garbe et al. 2008 Phase III (E) 1. Dacarbazine & IFN alfa-2a Not reported
2. Observation Superior OS
Eigentler et al. 2016 (ML17840) Phase III (C) Peginterferon alfa-2a Seems not superior Superior toxicity

Preceding treatment

Immunotherapy

24-month course

References

  1. Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K; Austrian Malignant Melanoma Cooperative Group. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. 1998 Apr;16(4):1425-9. link to original article contains verified protocol PubMed
  2. Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ; French Cooperative Group on Melanoma. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet. 1998 Jun 27;351(9120):1905-10. link to original article contains verified protocol PubMed
  3. Garbe C, Radny P, Linse R, Dummer R, Gutzmer R, Ulrich J, Stadler R, Weichenthal M, Eigentler T, Ellwanger U, Hauschild A. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol. 2008 Jun;19(6):1195-201. Epub 2008 Feb 14. link to original article contains protocol PubMed
  4. Hauschild A, Weichenthal M, Rass K, Linse R, Berking C, Böttjer J, Vogt T, Spieth K, Eigentler T, Brockmeyer NH, Stein A, Näher H, Schadendorf D, Mohr P, Kaatz M, Tronnier M, Hein R, Schuler G, Egberts F, Garbe C. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol. 2010 Feb 10;28(5):841-6. Epub 2010 Jan 4. link to original article contains protocol PubMed
  5. ML17840: Eigentler TK, Gutzmer R, Hauschild A, Heinzerling L, Schadendorf D, Nashan D, Hölzle E, Kiecker F, Becker J, Sunderkötter C, Moll I, Richtig E, Pönitzsch I, Pehamberger H, Kaufmann R, Pföhler C, Vogt T, Berking C, Praxmarer M, Garbe C; Dermatologic Cooperative Oncology Group (DeCOG). Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial. Ann Oncol. 2016 Aug;27(8):1625-32. Epub 2016 Jun 10. link to original article contains verified protocol PubMed

Interferon alfa-2b monotherapy

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HDI: High-Dose Interferon

Example orders

Variant #1, 3M, 6-month course

Study Evidence Comparator Comparative Efficacy
Cameron et al. 2001 (The Scottish study) Phase III (E) Observation Seems not superior

Note: The PubMed version of Cameron et al. 2001's abstract says that interferon alfa-2b is given "twice weekly," in contrast to what the actual paper says, "thrice weekly." This is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

Immunotherapy

6-month course

Variant #2, 3M, 18-month course

Study Evidence Comparator Comparative Efficacy
Grob et al. 2012 (EADO 2001/CMII) Phase III (C) Peginterferon x 36 mo Seems not superior

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

Preceding treatment

Immunotherapy

18-month course

Variant #3, 10M/5M, 24-month course

Study Evidence Comparator Comparative Efficacy
Eggermont et al. 2005 (EORTC 18952) Phase III (E) Observation Might have superior OS (*)

Note: efficacy is based on the 2016 update.

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Weeks 1 to 4: 10,000,000 units/m2 (route not specified) five times per week
    • Weeks 5 to 104: 5,000,000 units/m2 (route not specified) three times per week

24-month course

Variant #4, 10M/10M, 12-month course

Study Evidence Comparator Comparative Efficacy
Eggermont et al. 2005 (EORTC 18952) Phase III (E) Observation Might have superior OS (*)

Note: efficacy is based on the 2016 update.

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Weeks 1 to 4: 10,000,000 units/m2 (route not specified) five times per week
    • Weeks 5 to 52: 10,000,000 units/m2 (route not specified) three times per week

12-month course

Variant #5, 15M, 4-week course

Study Evidence Comparator Comparative Efficacy
Pectasides et al. 2009 Phase III (E) Interferon alfa-2b 15M/10M x 12 mo Non-inferior RFS

Preceding treatment

Immunotherapy

4-week course

Variant #6, 20M, 4-week course

Study Evidence Comparator Comparative Efficacy
Agarwala et al. 2017 (ECOG-ACRIN E1697) Phase III (E) Observation Seems not superior

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

Preceding treatment

Immunotherapy

4-week course

Variant #7, 20M/10M, 12-month course

Study Evidence Comparator Comparative Efficacy
Kirkwood et al. 1996 (ECOG E1684) Phase III (E) Observation Seems to have superior OS
Kirkwood et al. 2001 (ECOG E1694) Phase III (C) GM2-KLH/QS-21 vaccine Superior OS
Flaherty et al. 2014 (SWOG S0008) Phase III (C) Biochemotherapy Seems to have inferior RFS
Mohr et al. 2015 (DeCOG MM-ADJ-5) Phase III (C) Intermittent HDI Seems not superior
McMasters et al. 2016 (Sunbelt) Phase III (E) Observation Seems not superior

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Weeks 1 to 4: 20,000,000 units/m2 IV five times per week
    • Weeks 5 to 52: 10,000,000 units/m2 SC three times per week

12-month course

References

  1. ECOG E1684: Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7-17. link to original article contains verified protocol PubMed
  2. ECOG E1690: Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000 Jun;18(12):2444-58. link to original article PubMed
  3. ECOG E1694: Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, Rao U. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001 May 1;19(9):2370-80. link to original article contains verified protocol PubMed
  4. The Scottish Study: Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF; Scottish Melanoma Group. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001 May 4;84(9):1146-9. link to original article contains verified protocol link to PMC article PubMed
  5. EORTC 18952: Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. link to original article PubMed
    1. Update: Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G, Testori A; EORTC Melanoma Group. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016 Mar;55:111-21. link to original article PubMed
  6. Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, Kalofonos H, Fountzilas G, Panagiotou P, Kokkalis G, Papadopoulos O, Castana O, Papadopoulos S, Stavrinidis E, Vourli G, Ioannovich J, Gogas H. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol. 2009 Feb 20;27(6):939-44. Epub 2009 Jan 12. link to original article contains protocol PubMed
  7. EADO 2001/CMII: Grob JJ, Jouary T, Dréno B, Asselineau J, Gutzmer R, Hauschild A, Leccia MT, Landthaler M, Garbe C, Sassolas B, Herbst RA, Guillot B, Chene G, Pehamberger H. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study. Eur J Cancer. 2013 Jan;49(1):166-74. Epub 2012 Sep 10. link to original article contains protocol PubMed
  8. SWOG S0008: Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK. Southwest Oncology Group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of Cancer and Leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8. Epub 2014 Oct 20. link to original article link to PMC article contains verified protocol PubMed
  9. DeCOG MM-ADJ-5: Mohr P, Hauschild A, Trefzer U, Enk A, Tilgen W, Loquai C, Gogas H, Haalck T, Koller J, Dummer R, Gutzmer R, Brockmeyer N, Hölzle E, Sunderkötter C, Mauch C, Stein A, Schneider LA, Podda M, Göppner D, Schadendorf D, Weichenthal M. Intermittent high-dose intravenous interferon alfa-2b for adjuvant treatment of stage III melanoma: final analysis of a randomized phase III Dermatologic Cooperative Oncology Group trial. J Clin Oncol. 2015 Dec 1;33(34):4077-84. Epub 2015 Oct 26. link to original article contains verified protocol PubMed
  10. Sunbelt: McMasters KM, Egger ME, Edwards MJ, Ross MI, Reintgen DS, Noyes RD, Martin RC 2nd, Goydos JS, Beitsch PD, Urist MM, Ariyan S, Sussman JJ, Davidson BS, Gershenwald JE, Hagendoorn LJ, Stromberg AJ, Scoggins CR. Final results of the Sunbelt melanoma trial: a multi-institutional prospective randomized phase III study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J Clin Oncol. 2016 Apr 1;34(10):1079-86. Epub 2016 Feb 8. link to original article link to PMC article contains verified protocol PubMed
  11. ECOG-ACRIN E1697: Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III randomized study of 4 weeks of high-dose interferon-α-2b in stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article contains verified protocol PubMed

Ipilimumab monotherapy

Ipilimumab (Yervoy) for melanoma, adjuvant

Nivolumab monotherapy

Nivolumab (Opdivo) for melanoma, adjuvant

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Eilber et al. 1976 Randomized (C) BCG Seems to have inferior MFS
Veronesi et al. 1982 Phase III (C) 1. BCG Seems not superior
2. BCG & Dacarbazine Seems not superior
3. Dacarbazine Seems not superior
Quirt et al. 1991 Phase III (C) 1. BCG
2. BCG/Levamisole
 Seems not superior
3. Levamisole Might have inferior OS
Meyskens et al. 1994 (SWOG S8049) Phase III (C) Vitamin A Seems not superior
Creagan et al. 1995 Phase III (C) Interferon alfa-2a x 12 wk Seems not superior
Meyskens et al. 1995 (SWOG S8642) Phase III (C) Interferon gamma Seems not superior
Kirkwood et al. 1996 (ECOG E1684) Phase III (C) Interferon alfa-2b Seems to have inferior OS
Pehamberger et al. 1998 Phase III (C) Interferon alfa-2a x 12 m Seems to have inferior DFS
Grob et al. 1998 Phase III (C) Interferon alfa-2a x 18 m Might have inferior OS
Koops et al. 1998 (EORTC 18832) Phase III (C) Prophylactic ILP Seems not superior
Kirkwood et al. 2000 (ECOG E1690) Phase III (C) 1. HD-Interferon alfa-2b x 12 m Seems to have inferior RFS
2. LD-Interferon alfa-2b x 24 m Seems not superior
Cameron et al. 2001 (The Scottish study) Phase III (C) Interferon alfa-2b Seems not superior
Cascinelli et al. 2001 Phase III (C) Interferon alfa-2a Seems not superior
Sondak et al. 2002 Phase III (C) Allogeneic tumor vaccine Seems not superior
Hersey et al. 2002 Phase III (C) VMCL Might have inferior OS
Hancock et al. 2003 (AIM HIGH) Phase III (C) Interferon alfa-2a x 24 mo Seems not superior
Kleeberg et al. 2004 (EORTC 18871/DKG 80-1) Phase III (C) 1. Interferon alfa-2b x 12 mo
2. Interferon gamma
3. Iscador M 		Seems not superior
Agarwala et al. 2004 (ECOG E1673) Phase III (C) BCG Seems not superior
Eggermont et al. 2005 (EORTC 18952) Phase III (C) Interferon alfa-2b Might have inferior OS
Eggermont et al. 2008 (EORTC 18991) Phase III (C) Pegylated interferon alfa-2b Seems to have inferior RFS
Hansson et al. 2011 (Nordic IFN trial) Phase III (C) 1. Interferon alfa-2b x 12 mo
2. Interferon alfa-2b x 24 mo 		Seems not superior
Corrie et al. 2014 (AVAST-M) Phase III (C) Bevacizumab Seems not superior
Agarwala et al. 2017 (ECOG-ACRIN E1697) Phase III (C) Interferon alfa-2b Seems not superior

No treatment after primary resection.

Preceding treatment

References

  1. Eilber FR, Morton DL, Holmes EC, Sparks FC, Ramming KP. Adjuvant immunotherapy with BCG in treatment of regional-lymph-node metastases from malignant melanoma. N Engl J Med. 1976 Jan 29;294(5):237-40. link to original article PubMed
  2. Veronesi U, Adamus J, Aubert C, Bajetta E, Beretta G, Bonadonna G, Bufalino R, Cascinelli N, Cocconi G, Durand J, De Marsillac J, Ikonopisov RL, Kiss B, Lejeune F, MacKie R, Madej G, Mulder H, Mechl Z, Milton GW, Morabito A, Peter H, Priario J, Paul E, Rumke P, Sertoli R, Tomin R. A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med. 1982 Oct 7;307(15):913-6. link to original article PubMed
  3. Quirt IC, Shelley WE, Pater JL, Bodurtha AJ, McCulloch PB, McPherson TA, Paterson AH, Prentice R, Silver HK, Willan AR, Wilson K, Zee B. Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1991 May;9(5):729-35. link to original article PubMed
  4. SWOG S8049: Meyskens FL Jr, Liu PY, Tuthill RJ, Sondak VK, Fletcher WS, Jewell WR, Samlowski W, Balcerzak SP, Rector DJ, Noyes RD, Costanzi JJ. Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. J Clin Oncol. 1994 Oct;12(10):2060-5. link to original article PubMed
  5. Creagan ET, Dalton RJ, Ahmann DL, Jung SH, Morton RF, Langdon RM Jr, Kugler J, Rodrigue LJ. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol. 1995 Nov;13(11):2776-83. link to original article PubMed
  6. SWOG S8642: Meyskens FL Jr, Kopecky KJ, Taylor CW, Noyes RD, Tuthill RJ, Hersh EM, Feun LG, Doroshow JH, Flaherty LE, Sondak VK. Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. J Natl Cancer Inst. 1995 Nov 15;87(22):1710-3. link to original article PubMed
  7. ECOG E1684: Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7-17. link to original article contains verified protocol PubMed
  8. Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K; Austrian Malignant Melanoma Cooperative Group. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. 1998 Apr;16(4):1425-9. link to original article contains verified protocol PubMed
  9. Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ; French Cooperative Group on Melanoma. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet. 1998 Jun 27;351(9120):1905-10. link to original article contains verified protocol PubMed
  10. EORTC 18832: Koops HS, Vaglini M, Suciu S, Kroon BB, Thompson JF, Göhl J, Eggermont AM, Di Filippo F, Krementz ET, Ruiter D, Lejeune FJ; European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. J Clin Oncol. 1998 Sep;16(9):2906-12. link to original article PubMed
  11. ECOG E1690: Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000 Jun;18(12):2444-58. link to original article PubMed
  12. Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF; Scottish Melanoma Group. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001 May 4;84(9):1146-9. link to original article contains verified protocol link to PMC article PubMed
  13. Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet. 2001 Sep 15;358(9285):866-9. link to original article PubMed
  14. Sondak VK, Liu PY, Tuthill RJ, Kempf RA, Unger JM, Sosman JA, Thompson JA, Weiss GR, Redman BG, Jakowatz JG, Noyes RD, Flaherty LE. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol. 2002 Apr 15;20(8):2058-66. link to original article PubMed
  15. Hersey P, Coates AS, McCarthy WH, Thompson JF, Sillar RW, McLeod R, Gill PG, Coventry BJ, McMullen A, Dillon H, Simes RJ. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol. 2002 Oct 15;20(20):4181-90. link to original article PubMed
  16. AIM HIGH: Hancock BW, Wheatley K, Harris S, Ives N, Harrison G, Horsman JM, Middleton MR, Thatcher N, Lorigan PC, Marsden JR, Burrows L, Gore M. Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon alfa-2a in high-risk resected malignant melanoma. J Clin Oncol. 2004 Jan 1;22(1):53-61. Epub 2003 Dec 9. link to original article PubMed
  17. EORTC 18871/DKG 80-1: Kleeberg UR, Suciu S, Bröcker EB, Ruiter DJ, Chartier C, Liénard D, Marsden J, Schadendorf D, Eggermont AM; EORTC Melanoma Group in cooperation with the German Cancer Society (DKG). Final results of the EORTC 18871/DKG 80-1 randomised phase III trial: rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. 2004 Feb;40(3):390-402. link to original article PubMed
  18. ECOG E1673: Agarwala SS, Neuberg D, Park Y, Kirkwood JM. Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer. 2004 Apr 15;100(8):1692-8. link to original article PubMed
  19. EORTC 18952: Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. link to original article PubMed
    1. Update: Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G, Testori A; EORTC Melanoma Group. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016 Mar;55:111-21. link to original article PubMed
  20. EORTC 18991: Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-26. link to original article contains verified protocol PubMed
    1. Update: Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. Epub 2012 Sep 24. link to original article contains verified protocol PubMed
  21. Nordic IFN trial: Hansson J, Aamdal S, Bastholt L, Brandberg Y, Hernberg M, Nilsson B, Stierner U, von der Maase H; Nordic Melanoma Cooperative Group. Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Lancet Oncol. 2011 Feb;12(2):144-52. Epub 2011 Jan 20. link to original article PubMed
  22. AVAST-M: Corrie PG, Marshall A, Dunn JA, Middleton MR, Nathan PD, Gore M, Davidson N, Nicholson S, Kelly CG, Marples M, Danson SJ, Marshall E, Houston SJ, Board RE, Waterston AM, Nobes JP, Harries M, Kumar S, Young G, Lorigan P. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol. 2014 May;15(6):620-30. Epub 2014 Apr 15. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Lancet Oncol. 2014 Jun;15(7):e253. link to original article PubMed
  23. ECOG-ACRIN E1697: Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III randomized study of 4 weeks of high-dose interferon-α-2b in stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article PubMed

Peginterferon alfa-2b monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Eggermont et al. 2008 (EORTC 18991) Phase III (E) Observation Seems to have superior RFS

Patients enrolled in EORTC 18991 had resected stage III melanoma.

Preceding treatment

Immunotherapy

Given for up to 5 years if ECOG performance status remains 0 or 1

References

  1. EORTC 18991: Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-26. link to original article contains verified protocol PubMed
    1. Update: Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. Epub 2012 Sep 24. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Eggermont et al. 2018 (EORTC 1325/KEYNOTE-054) Phase III (E) Placebo Superior RFS

Preceding treatment

Immunotherapy

21-day cycle for 18 cycles

References

  1. EORTC 1325/KEYNOTE-054: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy Toxicity
Spitler & Sagabiel 1980 Phase III (C) Levamisole Seems not superior
Markovic et al. 2002 Phase III (C) Megestrol acetate Seems not superior
Eggermont et al. 2015 (EORTC 18071) Phase III (C) Ipilimumab Inferior OS (*) Similar HRQoL
Lawson et al. 2015 (ECOG-ACRIN E4697) Phase III (C) 1. GM-CSF
2. GM-CSF & Peptide vaccine
3. Peptide vaccine 		Seems not superior
Eggermont et al. 2018 (EORTC 1325) Phase III (C) Pembrolizumab Inferior RFS
Dreno et al. 2018 (DERMA) Phase III (C) MAGE-A3 antigen Seems not superior

No active antineoplastic treatment after primary resection. Placed here because one or more randomized clinical trials included a placebo in this disease context. Efficacy in EORTC 18071 is based on the 2016 update. While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinically relevance.

Preceding treatment

References

  1. Spitler LE, Sagebiel R. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. N Engl J Med. 1980 Nov 13;303(20):1143-7. link to original article PubMed
  2. Markovic S, Suman VJ, Dalton RJ, Woods JE, Fitzgibbons RJ Jr, Wold LE, Buckner JC, Kugler JW, Mailliard JA, Rowland KM, Krook JE, Brown DW, Tirona MT, Creagan ET. Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma. Am J Clin Oncol. 2002 Dec;25(6):552-6. link to original article PubMed
  3. 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, Gurunath RK, 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
    1. Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
    2. HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to PMC article PubMed
  4. ECOG-ACRIN E4697: Lawson DH, Lee S, Zhao F, Tarhini AA, Margolin KA, Ernstoff MS, Atkins MB, Cohen GI, Whiteside TL, Butterfield LH, Kirkwood JM. Randomized, placebo-controlled, phase III trial of yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) versus peptide vaccination versus GM-CSF plus peptide vaccination versus placebo in patients with no evidence of disease after complete surgical resection of locally advanced and/or stage IV melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network cancer research group (E4697). J Clin Oncol. 2015 Dec 1;33(34):4066-76. Epub 2015 Sep 8. link to original article link to PMC article PubMed
  5. EORTC 1325: 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
  6. DERMA: Dreno B, Thompson JF, Smithers BM, Santinami M, Jouary T, Gutzmer R, Levchenko E, Rutkowski P, Grob JJ, Korovin S, Drucis K, Grange F, Machet L, Hersey P, Krajsova I, Testori A, Conry R, Guillot B, Kruit WHJ, Demidov L, Thompson JA, Bondarenko I, Jaroszek J, Puig S, Cinat G, Hauschild A, Goeman JJ, van Houwelingen HC, Ulloa-Montoya F, Callegaro A, Dizier B, Spiessens B, Debois M, Brichard VG, Louahed J, Therasse P, Debruyne C, Kirkwood JM. MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Jul;19(7):916-929. Epub 2018 Jun 13. link to original article PubMed

Local therapy

Talimogene laherparepvec monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Andtbacka et al. 2015 Phase III (E) GM-CSF Superior DRR

Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions.

Immunotherapy

  • Talimogene laherparepvec (Imlygic) as follows:
    • Initially, to seroconvert HSV-seronegative patients: 106 pfu/mL SC intralesional injection once on day 1, then 108 pfu/mL SC intralesional injection once on day 22
    • Thereafter: 108 pfu/mL SC intralesional injection once every 2 weeks.
    • 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."

Generally given for at least 24 weeks. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.

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

References

  1. 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

Metastatic or unresectable disease

ABC

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

Regimen

Study Evidence Comparator Comparative Efficacy
Kottschade et al. 2013 (N0775) Randomized Phase II (E) Temozolomide & Bevacizumab Seems to have superior PFS6

The doses listed here are the amended starting doses.

Chemotherapy

28-day cycles

References

  1. 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. 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

Carboplatin & Paclitaxel

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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Variant #1, AUC 2/100

Study Evidence
Rao et al. 2006 Retrospective

Chemotherapy

28-day cycles

Variant #2, AUC 6/175

Study Evidence Comparator Comparative Efficacy
Weber et al. 2015 (CheckMate 037) Phase III (C) Nivolumab Inferior ORR (*)

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

Chemotherapy

21-day cycles

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

Study Evidence Comparator Comparative Efficacy
Hauschild et al. 2009 Phase III (C) Carboplatin, Paclitaxel, Sorafenib Seems not superior
Flaherty et al. 2013 (ECOG E2603) Phase III (C) Carboplatin, Paclitaxel, Sorafenib Seems not superior

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, until progression of disease, or unacceptable toxicity

Variant #4, 200/100, 6 out of 8 weeks

Study Evidence Comparator Comparative Efficacy
Zimpfer-Rechner et al. 2003 Randomized Phase II (E) Paclitaxel Seems not superior

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

8-week cycles

References

  1. Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D. 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
  2. Retrospective: Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article PubMed
  3. 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
  4. 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
  5. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article contains protocol PubMed
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed

Carboplatin & nab-Paclitaxel

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Regimen

Study Evidence
Kottschade et al. 2011 (N057E1) Phase II

Chemotherapy

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

  1. N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN. 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

Cisplatin & Dacarbazine

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Regimen

Study Evidence Comparator Comparative Efficacy
Ridolfi et al. 2002 Phase III (C) Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine Seems not superior

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

Chemotherapy

21-day cycle for 6 cycles

References

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

Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine

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Regimen

Study Evidence Comparator Comparative Efficacy
Ridolfi et al. 2002 Phase III (E) Cisplatin, Dacarbazine +/- Carmustine Seems not superior

Chemotherapy

  • Cisplatin (Platinol) 75 mg/m2 IV once on day 1
  • Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
  • Optional: Carmustine (BCNU) 100 mg/m2 (note: in Ridolfi et al. 2002, in contrast to the treatment text, figure 1 lists a dosage of 150 mg/m2) IV once on day 1
  • IL-2 - Aldesleukin (Proleukin) 4,500,000 units/m2 (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) SC on days 3 to 5, 8 to 12
  • Interferon alfa-2b (Intron-A) 3,000,000 units/m2 (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) IM on days 3 to 5 of week 1, then 3 times per week on all later weeks

21-day cycle for 6 cycles

References

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

Cisplatin, Dacarbazine, Paclitaxel

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Regimen

Study Evidence
Papadopoulos et al. 2009 Phase I/II

Note: cycle length is not specified in the abstract. This is the suggested phase II dosing.

Chemotherapy

Continued indefinitely

References

  1. Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II Study of a Cisplatin-Taxol-Dacarbazine Regimen in Metastatic Melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. link to original article contains protocol PubMed

CVD (Vinblastine)

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CVD: Cisplatin, Vinblastine, Dacarbazine

Variant #1, 20/1.2/800

Study Evidence Comparator Comparative Efficacy
Atkins et al. 2008 (ECOG E3695) Phase III (C) Sequential biochemotherapy Seems to have inferior PFS

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

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Variant #2, 20/1.6/800

Study Evidence
Legha et al. 1989 Phase II

Chemotherapy

21-day cycles

Variant #3, 20/2/800

Study Evidence Comparator Comparative Efficacy
Eton et al. 2002 Phase III (C) Sequential biochemotherapy Inferior TTP

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

Chemotherapy

21-day cycle for up to 10 cycles

References

  1. Legha SS, Ring S, Papadopoulos N, Plager C, Chawla S, Benjamin R. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer. 1989 Nov 15;64(10):2024-9. link to original contains protocol PubMed
  2. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. ECOG E3695: Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains verified protocol link to PMC article PubMed

CVD (Vindesine)

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CVD: Cisplatin, Vindesine, Dacarbazine

Regimen

Study Evidence Comparator Comparative Efficacy
Jungnelius et al. 1998 Phase III (E) Dacarbazine & Vindesine Superior TTP
Bajetta et al. 2006 Phase III (C) Biochemotherapy Seems not superior

Chemotherapy

21-day cycles

References

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

CVD, IL-2, IFN alfa-2b - sequential biochemotherapy

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CVD, IL-2, IFN alfa-2b: Cisplatin, Vinblastine, Dacarbazine, high-dose InterLeukin-2, InterFeroN alfa-2b
bioCT: bioChemoTherapy

Example orders

Variant #1, 4 cycles

Study Evidence Comparator Comparative Efficacy
McDermott et al. 2000 Phase II
Atkins et al. 2008 (ECOG E3695) Phase III (E) CVD Seems to have superior PFS

Chemoimmunotherapy

Supportive medications

21-day cycle for up to 4 cycles

Variant #2, 5 cycles

Study Evidence Comparator Comparative Efficacy
Eton et al. 2002 Phase III (E) CVD Superior TTP

Chemoimmunotherapy

42-day cycle for up to 5 cycles

Variant #3, 6 cycles

Study Evidence
Legha et al. 1998 Phase II

Chemoimmunotherapy

21-day cycle for 6 cycles

References

  1. Legha SS, Ring S, Eton O, Bedikian A, Buzaid AC, Plager C, Papadopoulos N. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998 May;16(5):1752-9. link to original article contains protocol PubMed
  2. McDermott DF, Mier JW, Lawrence DP, van den Brink MR, Clancy MA, Rubin KM, Atkins MB. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res. 2000 Jun;6(6):2201-8. link to original article contains verified protocol PubMed
  3. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains verified protocol PubMed
  4. ECOG E3695: Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains verified protocol link to PMC article PubMed

Dacarbazine monotherapy

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Example orders

Variant #1, 850 mg/m2 q3wk

Study Evidence Comparator Comparative Efficacy
Pritchard et al. 1980 Phase II
Robert et al. 2011 (CA184-024) Phase III (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

21-day cycle for 8 cycles

Variant #2, 850 mg/m2 q4wk

Study Evidence Comparator Comparative Efficacy
Schadendorf et al. 2006 Phase III (C) Dendritic cell vaccine Seems not superior

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

Chemotherapy

28-day cycles

Variant #3, 900 mg/m2 q3wk

Study Evidence Comparator Comparative Efficacy
Daponte et al. 2013 (SICOG 0109) Phase III (C) 1. Dacarbazine & Fotemustine
2. Dacarbazine & IFN
3. Dacarbazine, Fotemustine, IFN 		Seems not superior

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

Chemotherapy

21-day cycles

Variant #4, 1000 mg/m2 q3wk

Study Evidence Comparator Comparative Efficacy
Chapman et al. 1999 Phase III (C) Dartmouth regimen Might have inferior ORR
Bedikian et al. 2010 Phase III (C) DHA-paclitaxel Seems not superior
Patel et al. 2011 (EORTC 18032) Phase III (C) Temozolomide Seems not superior
Chapman et al. 2011 (BRIM-3) Phase III (C) Vemurafenib Inferior OS
Hauschild et al. 2012 (BREAK-3) Phase III (C) Dabrafenib Inferior PFS
Flaherty et al. 2012 (METRIC) Phase III (C) Trametinib Seems to have inferior OS
Ribas et al. 2013 (A3671009) Phase III (C) Tremelimumab Seems not superior
Robert et al. 2014 (CheckMate 066) Phase III (C) Nivolumab Inferior OS
Weber et al. 2015 (CheckMate 037) Phase III (C) Nivolumab Inferior ORR (*)
Hersh et al. 2015 Phase III (C) nab-Paclitaxel Seems to have inferior PFS
Dummer et al. 2017 (NEMO) Phase III (C) Binimetinib Inferior PFS
Ugurel et al. 2017 Phase III (C) Chemosensitivity-directed therapy Seems not superior

Note: CheckMate 037 did not meet the co-primary endpoint of OS. Patients in BRIM-3 had a BRAF p.V600E mutation detected. Patients in NEMO had NRAS mutations.

Chemotherapy

21-day cycles

Variant #5, 1000 mg/m2, split doses, q4wk

Study Evidence Comparator Comparative Efficacy
Falkson et al. 2003 Phase III (C) 1. DTIC & Interferon
2. DTIC & Tamoxifen
3. DTIC, Interferon, Tamoxifen 		Seems to have inferior ORR

Chemotherapy

28-day cycles

Variant #6, 1250 mg/m2, split doses, q3wk

Study Evidence Comparator Comparative Efficacy
Cocconi et al. 1992 Phase III (C) Dacarbazine & Tamoxifen Seems to have inferior OS
Middleton et al. 2000b Phase III (C) Temozolomide Seems not superior

Chemotherapy

21-day cycles

Variant #7, 1250 mg/m2, split doses, q4wk

Study Evidence Comparator Comparative Efficacy
Avril et al. 2004 Phase III (C) Fotemustine Seems to have inferior ORR

Chemotherapy

28-day cycles

Variant #8, 2500 mg/m2, split doses, q4wk

Study Evidence Comparator Comparative Efficacy
Luikart et al. 1984 Phase III (C) VBD Seems not superior

Chemotherapy

28-day cycles

References

  1. Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
  2. Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article contains verified protocol PubMed
  3. Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains verified protocol PubMed
  4. Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH. 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
  5. 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
  6. 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
  7. 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
  8. 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; DC study group of the 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
  9. 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
  10. 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
  11. BRIM-3: Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. link to original article contains verified protocol link to PMC article PubMed
    1. Update: McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. Epub 2014 Feb 7. link to PMC article PubMed
  12. 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
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
  13. BREAK-3: Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25. link to original article contains verified protocol PubMed
  14. METRIC: Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
  15. 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
  16. 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 (SICOG). 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
  17. 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
    1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2018 Oct 25. [Epub ahead of print] link to original article PubMed
  18. 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
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed
  19. 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 PubMed
  20. NEMO: Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozón V, Long GV, Flaherty K. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. Epub 2017 Mar 8. link to original article contains protocol PubMed
  21. 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

Dacarbazine & Interferon alfa

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Regimen

Study Evidence Comparator Comparative Efficacy
Middleton et al. 2000a Phase III (C) DBCT Seems not superior
Hauschild et al. 2001 Phase III (C) Dacarbazine, IFN alfa, IL-2 Seems not superior

Chemotherapy

References

  1. Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM, Harper P, Thatcher N. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer. 2000 Mar;82(6):1158-62. link to original article link to PMC article PubMed
  2. Hauschild A, Garbe C, Stolz W, Ellwanger U, Seiter S, Dummer R, Ugurel S, Sebastian G, Nashan D, Linse R, Achtelik W, Mohr P, Kaufmann R, Fey M, Ulrich J, Tilgen W. Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer. 2001 Apr 20;84(8):1036-42. link to original article link to PMC article PubMed

Dacarbazine & Ipilimumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Robert et al. 2011 (CA184-024) Phase III (E) Dacarbazine Superior OS

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment

References

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

Docetaxel monotherapy

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Regimen

Study Evidence
Aamdal et al. 1994 Phase II

Chemotherapy

Supportive medications

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

21-day cycles

References

  1. Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J. 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. contains protocol PubMed

Fotemustine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Avril et al. 2004 Phase III (E) 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

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

High-dose Interleukin-2

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HD IL-2: High-Dose InterLeukin-2

Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Sparano et al. 1993 Phase III (C) HD IL-2 & IFN alfa-2a Seems not superior
Rosenberg et al. 1994 Case series
Atkins et al. 1999 Phase II
Schwartzentruber et al. 2011 Phase III (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) 600,000 or 720,000 units/kg IV 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

6 to 12 weeks per cycle for up to 5 cycles

References

  1. Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. link to original article PubMed
  2. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article PubMed
  3. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. link to original article contains verified protocol PubMed
    1. Update: Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. PubMed
  4. 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 PubMed

Low-dose Interleukin-2

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LD IL-2: Low-Dose InterLeukin-2

Regimen

Study Evidence Comparator Efficacy
Agarwala et al. 2002 Phase III (C) LD IL-2 & Histamine Inferior OS

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) as follows:
    • Weeks 1 & 3: 9,000,000 units SC twice per day on days 1 & 2
    • Weeks 2 & 4: 2,000,000 units SC twice per day on days 1 to 5

6-week cycles

References

  1. Agarwala SS, Glaspy J, O'Day SJ, Mitchell M, Gutheil J, Whitman E, Gonzalez R, Hersh E, Feun L, Belt R, Meyskens F, Hellstrand K, Wood D, Kirkwood JM, Gehlsen KR, Naredi P. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol. 2002 Jan 1;20(1):125-33. link to original article PubMed

Imatinib monotherapy

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Variant #1

Study Evidence
Hodi et al. 2013 Phase II

Patients had melanomas arising from mucosal, acral, and chronically sun-damaged skin with KIT mutations or amplifications.

Starting dose

Given until disease progression; then proceed to higher dose:

Higher dose

Given until disease progression

Variant #2

Study Evidence
Carvajal et al. 2011 Phase II

Patients had melanomas arising from mucosal, acral, and chronically sun-damaged skin with KIT mutations or amplifications.

Chemotherapy

Given until disease progression

References

  1. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011 Jun 8;305(22):2327-34. contains protocol link to PMC article PubMed
  2. Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, Weber JS, Gajewski TF, O'Day SJ, Kim KB, Lawrence D, Flaherty KT, Luke JJ, Collichio FA, Ernstoff MS, Heinrich MC, Beadling C, Zukotynski KA, Yap JT, Van den Abbeele AD, Demetri GD, Fisher DE. Imatinib for Melanomas Harboring Mutationally Activated or Amplified KIT Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin. J Clin Oncol. 2013 Sep 10;31(26):3182-90. Epub 2013 Jun 17. link to original article contains verified protocol link to PMC article PubMed

Ipilimumab monotherapy

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Example orders

Variant #1, 3 mg/kg

FDA-recommended dose
Study Evidence Comparator Efficacy Toxicity
Hodi et al. 2010 (MDX010-20) Phase III (E) 1. Ipilimumab & gp100 peptide vaccine Seems not superior
2. gp100 peptide vaccine Superior OS
Robert et al. 2015 (KEYNOTE-006) Phase III (C) 1. Pembrolizumab 10 mg/kg q2wks Inferior OS
2. Pembrolizumab 10 mg/kg q3wks Inferior OS
Postow et al. 2015 (CheckMate 069) Phase III (C) Ipilimumab & Nivolumab Inferior PFS
Larkin et al. 2015 (CheckMate 067) Phase III (C) 1. Ipilimumab & Nivolumab Inferior OS (*) Equivalent HRQoL
2. Nivolumab Inferior OS (*) Equivalent HRQoL
Ascierto et al. 2017 Phase III (C) Ipilimumab 10 mg/kg Seems to have inferior OS

Note: reported efficacy for CheckMate 067 is based on the 2018 update.

Immunotherapy

21-day cycle for 4 cycles

Variant #2, 10 mg/kg

Study Evidence Comparator Comparative Efficacy
Weber et al. 2008 Phase I/II
Wolchok et al. 2010 Phase II
O'Day et al. 2010 Phase II
Margolin et al. 2012 Phase II
Hodi et al. 2014 (ECOG E1608) Randomized Phase II (C) Ipilimumab & Sargramostim Inferior OS
Ascierto et al. 2017 Phase III (C) Ipilimumab 3 mg/kg Seems to have superior OS

Note: In Wolchok et al. 2010, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • O'Day et al. 2010 & Margolin et al. 2012: Patients who were clinically stable could proceed to ipilimumab maintenance

References

  1. Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. link to original article PubMed
  2. 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
  3. MDX010-20: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains verified protocol link to PMC article PubMed
    1. Update: McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. link to original article PubMed
  4. 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
  5. 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
  6. ECOG E1608: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. link to original article link to PMC article contains protocol PubMed
  7. KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains verified protocol PubMed
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
  8. 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 PubMed
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
  9. 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
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
    2. 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
  10. 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

Ipilimumab & Nivolumab

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Variant #1

Study Evidence Comparator Efficacy Toxicity
Larkin et al. 2015 (CheckMate 067) Phase III (E) 1. Ipilimumab Superior OS (*) Equivalent HRQoL
2. Nivolumab Superior PFS Equivalent HRQoL

Note: reported efficacy for the comparison marked with (*) is based on the 2018 update.

Immunotherapy, part 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 cycles

Variant #2

Study Evidence Comparator Comparative Efficacy
Wolchok et al. 2013 (CA209-004) Phase 1
Postow et al. 2015 (CheckMate 069) Phase III (E) Ipilimumab Superior PFS

These doses were from the cohort deemed by Wolchok et al. 2013 as being "the maximum doses that were associated with an acceptable level of adverse events."

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

21-day cycle for 4 cycles

Subsequent treatment

References

  1. 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 PubMed
  2. 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 PubMed
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
  3. 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
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
    2. 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

Ipilimumab, then Nivolumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Weber et al. 2016 (CheckMate 064) Randomized Phase II (E) Nivolumab, then Ipilimumab Seems to have inferior OS

Immunotherapy, part 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

  1. 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

Nivolumab monotherapy

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Variant #1, limited duration

Study Evidence
Weber et al. 2013 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

Variant #2, indefinite

Study Evidence Comparator Efficacy Toxicity
Robert et al. 2014 (CheckMate 066) Phase III (E) Dacarbazine Superior OS
Weber et al. 2015 (CheckMate 037) Phase III (E) 1. Dacarbazine
2. Carboplatin & Paclitaxel 		Superior ORR (*)
Larkin et al. 2015 (CheckMate 067) Phase III (E) 1. Ipilimumab Superior OS (*) Equivalent HRQoL
2. Ipilimumab & Nivolumab Inferior PFS Equivalent HRQoL

Note: CheckMate 037 did not meet the co-primary endpoint of OS. Reported efficacy for the CheckMate 067 comparison marked with (*) is based on the 2018 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

References

  1. Phase I: 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. contains verified protocol link to PMC article PubMed
  2. 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
    1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2018 Oct 25. [Epub ahead of print] link to original article PubMed
  3. 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
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed
  4. 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
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
    2. 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

Nivolumab, then Ipilimumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Weber et al. 2016 (CheckMate 064) Randomized Phase II (E) 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

21-day cycle for 4 cycles

Subsequent treatment

References

  1. 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

Paclitaxel monotherapy

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Example orders

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

Study Evidence Comparator Comparative Efficacy
O'Day et al. 2013 (SYMMETRY) Phase III (C) Elesclomol & Paclitaxel Seems not superior
Hamid et al. 2014 Phase III (C) Tasisulam Seems not superior

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

28-day cycles

Variant #2, 175 mg/m2 q3wk

Study Evidence Comparator Comparative Efficacy
Flaherty et al. 2012 (METRIC) Phase III (C) Trametinib Seems to have inferior OS

This was a therapy option for patients in the control arm of METRIC. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles

Variant #3, 250 mg/m2 q3wk

Study Evidence
Legha et al. 1990 Phase II

Chemotherapy

21-day cycles

References

  1. Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. link to original article contains protocol PubMed
  2. METRIC: Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
  3. 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
  4. 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

Paclitaxel, nanoparticle albumin-bound monotherapy

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Variant #1

Study Evidence Comparator Comparative Efficacy
Hersh et al. 2012 Phase II
Hersh et al. 2015 Phase III (E) Dacarbazine Seems to have superior PFS

Chemotherapy

28-day cycles

Variant #2

Study Evidence
Hersh et al. 2012 Phase II

Note: this dose was intended for previously treated patients.

Chemotherapy

28-day cycles

References

  1. Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. link to original article contains protocol PubMed
  2. 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 PubMed

Pembrolizumab monotherapy

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Variant #1, 2 mg/kg q3wk

Study Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001) Phase I, >20 pts
Ribas et al. 2015 (KEYNOTE-002) Randomized Phase II (E) Investigator-choice of:
1. Carboplatin & Paclitaxel
2. Dacarbazine
3. Paclitaxel
4. Temozolomide 		Superior PFS
5. Pembrolizumab 10 mg/kg q3wk Seems not superior

Immunotherapy

21-day cycles

Variant #2, 10 mg/kg q2wk

Study Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001) Phase I, >20 pts
Robert et al. 2015 (KEYNOTE-006) Phase III (E) 1. Ipilimumab Superior OS
2. Pembrolizumab 10 mg/kg q3wk Seems not superior

Immunotherapy

14-day cycles

Variant #3, 10 mg/kg q3wk

Study Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001) Phase I, >20 pts
Ribas et al. 2015 (KEYNOTE-002) Randomized Phase II (E) Investigator-choice of:
1. Carboplatin & Paclitaxel
2. Dacarbazine
3. Paclitaxel
4. Temozolomide 		Superior PFS
5. Pembrolizumab 2 mg/kg Seems not superior
Robert et al. 2015 (KEYNOTE-006) Phase III (E) 1. Ipilimumab Superior OS
2. Pembrolizumab 10 mg/kg q2wk Seems not superior

Immunotherapy

21-day cycles

References

  1. 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
    1. Update: Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
    2. Update: Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. link to original article PubMed
  2. KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. link to original article contains verified protocol PubMed
  3. KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains verified protocol PubMed
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Eisen et al. 2010 Phase III (C) Lenalidomide Seems not superior

No active antineoplastic treatment.

References

  1. Eisen T, Trefzer U, Hamilton A, Hersey P, Millward M, Knight RD, Jungnelius JU, Glaspy J. Results of a multicenter, randomized, double-blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma. Cancer. 2010 Jan 1;116(1):146-54. link to original article PubMed

Temozolomide monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Middleton et al. 2000b Phase III (E) Dacarbazine Seems not superior
Ribas et al. 2013 (A3671009) Phase III (C) Tremelimumab Seems not superior

Chemotherapy

28-day cycles

References

  1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
  2. 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

Temozolomide & Bevacizumab

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TB: Temozolomide & Bevacizumab

Regimen

Study Evidence Comparator Comparative Efficacy
Kottschade et al. 2013 (N0775) Randomized Phase II (E) ABC Seems to have inferior PFS6

Chemotherapy

28-day cycles

References

  1. 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. 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

Maintenance immunotherapy for metastatic or unresectable disease

IL-2 monotherapy

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Example orders

Regimen

Study Evidence
O'Day et al. 2002 Phase II

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

Supportive medications

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, then 18,000,000 units/m2 IV continuous infusion over 12 hours, then 18,000,000 units/m2 IV continuous infusion over 24 hours on days 1 to 2
    • Then as an outpatient: 1,000,000 units/m2 SC once per day every Monday to Friday on days 3 to 28

Supportive medications

28-day cycles, alternating with low-dose cycles, for a total of 12 cycles

References

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

Ipilimumab monotherapy

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Regimen

Study Evidence
O'Day et al. 2010 Phase II
Robert et al. 2011 (CA184-024) Non-randomized portion of RCT
Margolin et al. 2012 Phase II

Preceding treatment

Immunotherapy

12-week cycles

References

  1. 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
  2. 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
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
  3. 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

Ipilimumab & Nivolumab

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Regimen

Study Evidence
Postow et al. 2015 (CheckMate 069) Non-randomized portion of RCT

Preceding treatment

Immunotherapy

12-week cycle for 8 cycles

References

  1. CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed

Nivolumab monotherapy

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Variant #1, indefinite

Study Evidence
Weber et al. 2016 (CheckMate 064) 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

Variant #2, 2-year course

Study Evidence
Weber et al. 2013 Phase I

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 2 years

References

  1. Phase I: 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. contains verified protocol link to PMC article PubMed
  2. 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
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