Melanoma
Section editor | |
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Elizabeth Buchbinder, MD Dana-Farber Cancer Institute Boston, MA |
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
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Guidelines
EDF/EADO/EORTC
- 2016: Garbe et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016 PubMed
ESMO
- 2015: Dummer et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. PubMed
INMC
- 2019: Amaria et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium
NCCN
Neoadjuvant response criteria
- 2018: Tetzlaff et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma
Adjuvant therapy
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
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, given first
- Vinblastine (Velban) 1.2 mg/m2 IV push once per day on days 1 to 4, given second
- Dacarbazine (DTIC) 800 mg/m2 IV over 60 minutes once on day 1, given third
Immunotherapy
- IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m2)
- Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day on days 1 to 5, 8, 10, 12
- Doses on days 8, 10, 12 are given as outpatient doses
21-day cycle for 3 cycles
References
- 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:
- Cycles 1 to 3: 3,000,000 international units SC once per day
- Cycles 4 to 52: 3,000,000 international units SC once per day on days 1, 3, 5
7-day cycle for 52 cycles (1 year)
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
- Interferon alfa-2a (Roferon-A) 3,000,000 international units SC once per day on days 1, 3, 5
7-day cycle for 78 cycles (18 months)
Variant #3, 24 months
Study | Evidence | Comparator | Comparative Efficacy | Comparative 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
- Surgery, within 3 months
Immunotherapy
- Interferon alfa-2a (Roferon-A) 3,000,000 international units SC once per day on days 1, 3, 5
7-day cycle for 104 cycles (2 years)
References
- 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
- 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
- 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
- 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
- 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
- Interferon alfa-2b (Intron-A) 3,000,000 units SC three times per week
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
- Interferon alfa-2b (Intron-A) 3,000,000 units SC three times per week
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
- Interferon alfa-2b (Intron-A) 15,000,000 units/m2 IV five times per week
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
- Interferon alfa-2b (Intron-A) 20,000,000 units/m2 IV five times per week
4-week course
Variant #7, 20M/10M, 12-month course
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Kirkwood et al. 1996 (ECOG E1684) | Phase III (E-RT) | Observation | Seems to have superior OS |
Kirkwood et al. 2000 (ECOG E1690) | Phase III (E-RT) | Observation | Seems to have superior RFS |
2. LD-Interferon alfa-2b; 24 mo | Seems not superior | ||
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 |
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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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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-RT) | Observation | Seems to have superior RFS |
Patients enrolled in EORTC 18991 had resected stage III melanoma. Given for up to 5 years if ECOG performance status remains 0 or 1.
Preceding treatment
Immunotherapy
- Peginterferon alfa-2b (Sylatron) as follows:
- Cycles 1 & 2: 6 mcg/kg SC once per day on days 1, 8, 15, 22
- Cycles 3 to 65: 3 mcg/kg SC once per day on days 1, 8, 15, 22
28-day cycle for 65 cycles (5 years)
References
- 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
- 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-RT) | Placebo | Superior RFS |
Preceding treatment
- Complete regional lymphadenectomy, within 13 weeks
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for 18 cycles
References
- EORTC 1325/KEYNOTE-054: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains verified protocol PubMed
Placebo
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Regimen
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Spitler & Sagabiel 1980 | Phase III (C) | Levamisole | Seems not superior | |
Wallack et al. 1995 | Phase III (C) | VMO | 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
- Spitler & Sagabiel 1980: Surgery
- EORTC 18071: Complete regional lymphadenectomy, within 12 weeks
- ECOG-ACRIN E4697: Complete resection, within 16 weeks
- EORTC 1325: Complete regional lymphadenectomy, within 13 weeks
References
- 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
- Wallack MK, Sivanandham M, Balch CM, Urist MM, Bland KI, Murray D, Robinson WA, Flaherty LE, Richards JM, Bartolucci AA, Rosen L. A phase III randomized, double-blind multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma. Cancer. 1995 Jan 1;75(1):34-42. link to original article PubMed
- Update: Wallack MK, Sivanandham M, Ditaranto K, Shaw P, Balch CM, Urist MM, Bland KI, Murray D, Robinson WA, Flaherty L, Richards JM, Rosen L, Bartolucci AA. Increased survival of patients treated with a vaccinia melanoma oncolysate vaccine: second interim analysis of data from a phase III, multi-institutional trial. Ann Surg. 1997 Aug;226(2):198-206. link to original article link to PMC article PubMed
- 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
- 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
- Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
- HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to PMC article PubMed
- 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
- 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
- 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 (OPTiM) | Phase III (E) | GM-CSF | Seems to have superior OS (*) |
Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions. Reported efficacy is based on the 2019 update.
Immunotherapy
- Talimogene laherparepvec (Imlygic) as follows:
- Initially, to seroconvert HSV-seronegative patients: 1,000,000 pfu/mL SC intralesional injection once on day 1
- Thereafter: 100,000,000 pfu/mL SC intralesional injection once on day 1
- Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."
21-day cycle for 1 cycle, then 14-day cycle for at least 12 cycles
Subsequent treatment
- Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months
References
- OPTiM: Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. link to original article contains verified protocol PubMed
- Update: Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. link to original article link to PMC article PubMed
Metastatic or unresectable disease
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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 80 mg/m2 IV once per day on days 1, 8, 15
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
28-day cycles
References
- 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
- Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
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
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
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
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
- Carboplatin (Paraplatin) 200 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
References
- Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. link to original article contains protocol PubMed
- Retrospective: Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article PubMed
- 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
- 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
- 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
- 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
- Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, given second
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first
Supportive medications
- "All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
References
- N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN. 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
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
21-day cycle for 6 cycles
References
- Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains verified protocol PubMed
Cisplatin, Dacarbazine, 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
Immunotherapy
- 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 once per day 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
- 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
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 120 mg/m2 IV once per day on days 1 & 8
Continued indefinitely
References
- Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. link to original article contains protocol PubMed
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
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, given first
- Vinblastine (Velban) 1.2 mg/m2 IV push once per day on days 1 to 4, given second
- Dacarbazine (DTIC) 800 mg/m2 IV over 60 minutes once on day 1, given third
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
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 2 to 5
- Vinblastine (Velban) 1.6 mg/m2 IV once per day on days 1 to 5
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
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
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4
- Vinblastine (Velban) 2 mg/m2 IV once per day on days 1 to 4
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
21-day cycle for up to 10 cycles
References
- 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
- 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
- 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
- Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1 to 3
- Vindesine (Eldisine) 2.5 mg/m2 IV once on day 1
- Dacarbazine (DTIC) 250 mg/m2 IV once per day on days 1 to 3
21-day cycles
References
- Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. link to original article PubMed
- Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. link to original article PubMed
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 |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, given first
- Vinblastine (Velban) 1.2 mg/m2 IV push once per day on days 1 to 4, given second
- Dacarbazine (DTIC) 800 mg/m2 IV over 60 minutes once on day 1, given third
Immunotherapy
- IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m2)
- Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day on days 1 to 5, 8, 10, 12
- Doses on days 8, 10, 12 are given as outpatient doses
Supportive medications
- All antihypertensive therapy discontinued at least 24 hours before each cycle
- Cephalexin (Keflex) or Ciprofloxacin (Cipro) 250 mg PO twice per day on days 1 to 14
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 16, or until ANC greater than 10,000/uL
- Ondansetron (Zofran) 32 mg IV once per day
- Lorazepam (Ativan) 1 mg IV or PO every 6 hours
- Acetaminophen (Tylenol) 650 mg PO every 6 hours
- Ranitidine (Zantac) 150 mg PO every 12 hours
- Hydroxyzine (Atarax) 25 to 50 mg PO or Diphenhydramine (Benadryl) 25 mg PO every 6 hours for pruritis
- Meperidine (Demerol) 25 to 50 mg IV every 3 hours for chills and rigors
- Antidiarrheals & anxiolytics as needed
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 |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4, 22 to 25
- Vinblastine (Velban) 1.5 mg/m2 IV once per day on days 1 to 4, 22 to 25
- Dacarbazine (DTIC) 800 mg/m2 IV once per day on days 1 & 22
Immunotherapy
- IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours, started on days 5, 17, 26 (total dose per cycle: 108,000,000 units/m2)
- Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day on days 5 to 9, 17 to 21, 26 to 30
42-day cycle for up to 5 cycles
Variant #3, 6 cycles
Study | Evidence |
---|---|
Legha et al. 1998 | Phase II |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4
- Vinblastine (Velban) 1.6 mg/m2 IV once per day on days 1 to 4
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
Immunotherapy
- IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m2)
- Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day on days 1 to 5
21-day cycle for 6 cycles
References
- 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
- 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
- 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
- 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
- Dacarbazine (DTIC) 850 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Variant #2, 850 mg/m2 q4wk
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Schadendorf et al. 2006 | Phase III (C) | Autologous peptide-pulsed monocyte-derived dendritic cells | 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
- Dacarbazine (DTIC) 850 mg/m2 IV once on day 1
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
- Dacarbazine (DTIC) 900 mg/m2 IV once on day 1
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 |
Testori et al. 2008 (C-100-21) | Phase III (C) | Vitespen | Seems not superior |
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
- Dacarbazine (DTIC) 1000 mg/m2 IV once on day 1
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
- Dacarbazine (DTIC) 200 mg/m2 IV once per day on days 1 to 5
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
- Dacarbazine (DTIC) 250 mg/m2 IV over 20 to 30 minutes once per day on days 1 to 5
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
- Dacarbazine (DTIC) 250 mg/m2 IV over 20 to 30 minutes once per day on days 1 to 5
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
- Dacarbazine (DTIC) 250 mg/m2 IV once per day on days 1 to 10
28-day cycles
References
- Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
- Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article contains verified protocol PubMed
- Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains verified protocol PubMed
- 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
- Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. link to original article contains protocol PubMed
- Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
- Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains verified protocol PubMed
- 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
- C-100-21: Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. link to original article does not contain protocol PubMed
- Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. link to original article link to PMC article contains protocol PubMed
- EORTC 18032: Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; EORTC Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. link to original article contains protocol PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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-2a
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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 |
Note: in Hauschild et al. 2001, the interferon is described as "IFN-α2a/b" without further details.
Chemotherapy
Immunotherapy
References
- 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
- 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
- Dacarbazine (DTIC) 850 mg/m2 IV once on day 1
- Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 10 mg/kg IV once on day 1
21-day cycle for 8 cycles
Subsequent treatment
- SD or better: Ipilimumab maintenance
References
- CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed
- 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
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
Supportive medications
- "No prophylactic treatment with steroids or antihistamines was given."
21-day cycles
References
- Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J. 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
- 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 | Non-randomized | ||
Atkins et al. 1999 | Phase II (RT) | ||
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
- Included:
- Acetaminophen (Tylenol)
- Indomethacin (Indocin)
- Meperidine (Demerol)
- Ranitidine (Zantac)
- Cimetidine (Tagamet)
- Hydroxyzine (Atarax)
- Diphenhydramine (Benadryl)
- Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
6- to 12-week cycle for up to 5 cycles
References
- Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. link to original article PubMed
- Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article PubMed
- Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. link to original article contains verified protocol PubMed
- Update: Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. PubMed
- 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
- 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, pre-planned escalation
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.
Chemotherapy
- Imatinib (Gleevec) as follows:
- Starting dose: 400 mg PO once per day
- Upon progression: 400 mg PO twice per day
Continued indefinitely
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
- Imatinib (Gleevec) 400 mg PO twice per day
Continued indefinitely
References
- 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
- 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 | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Hodi et al. 2010 (MDX010-20) | Phase III (E-RT) | 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
- Ipilimumab (Yervoy) 3 mg/kg IV over 90 minutes once on day 1
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
- Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
- CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
- HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
- Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
- 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 | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Larkin et al. 2015 (CheckMate 067) | Phase III (E-RT) | 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
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1
21-day cycle for 4 cycles, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day 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
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1, given second
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first
21-day cycle for 4 cycles, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
References
- Phase I: Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. link to original article contains verified protocol link to supplementary appendix PubMed
- 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
- Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
- CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
- HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
- Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
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
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 6 cycles
Subsequent treatment
References
- 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 | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Robert et al. 2014 (CheckMate 066) | Phase III (E-RT) | Dacarbazine | Superior OS | |
Weber et al. 2015 (CheckMate 037) | Phase III (E-RT) | 1. Dacarbazine 2. Carboplatin & Paclitaxel |
Superior ORR (*) | |
Larkin et al. 2015 (CheckMate 067) | Phase III (E-RT) | 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
- 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
- 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
- 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
- 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
- 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
- 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
- HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
- Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
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
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
References
- 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
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
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
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
Variant #3, 250 mg/m2 q3wk
Study | Evidence |
---|---|
Legha et al. 1990 | Phase II |
Chemotherapy
- Paclitaxel (Taxol) 250 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
References
- Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. link to original article contains protocol PubMed
- 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
- 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
- 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
nab-Paclitaxel 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Variant #2
Study | Evidence |
---|---|
Hersh et al. 2012 | Phase II |
Note: this dose was intended for previously treated patients.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. link to original article contains protocol PubMed
- 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-RT) | Investigator-choice of: 1. Carboplatin & Paclitaxel 2. Dacarbazine 3. Paclitaxel 4. Temozolomide |
Superior PFS |
5. Pembrolizumab 10 mg/kg q3wk | Seems not superior |
Immunotherapy
- Pembrolizumab (Keytruda) 2 mg/kg IV over 30 minutes once on day 1
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-RT) | 1. Ipilimumab | Superior OS |
2. Pembrolizumab 10 mg/kg q3wk | Seems not superior |
Immunotherapy
- Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1
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-RT) | 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-RT) | 1. Ipilimumab | Superior OS |
2. Pembrolizumab 10 mg/kg q2wk | Seems not superior |
Immunotherapy
- Pembrolizumab (Keytruda) 10 mg/kg IV over 30 minutes once on day 1
21-day cycles
Variant #4, 200 mg q3wk
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Long et al. 2019 (ECHO-301/KEYNOTE-252) | Phase III (C) | Epacadostat & Pembrolizumab | Seems not superior |
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg/kg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
References
- Phase 1: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. link to original article link to PMC article PubMed
- Update: Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
- Update: Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. link to original article PubMed
- Update: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. link to original article link to PMC article PubMed
- KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. link to original article contains verified protocol PubMed
- KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains verified protocol PubMed
- 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
- ECHO-301/KEYNOTE-252: Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. link to original article contains protocol PubMed
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
- 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 |
Kaufmann et al. 2005 | Phase III (C) | Temozolomide & Interferon-alfa | Seems to have inferior ORR |
Ribas et al. 2013 (A3671009) | Phase III (C) | Tremelimumab | Seems not superior |
Chemotherapy
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5, taken while fasting
28-day cycles
References
- Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
- Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. link to original article contains protocol PubMed
- A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains verified protocol link to PMC article PubMed
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
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- 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 |
Preceding treatment
- Induction biochemotherapy
Immunotherapy, low-dose cycles (1, 4, 7, 9, 11)
- IL-2 - Aldesleukin (Proleukin) 1,000,000 units/m2 SC once per day every Monday to Friday on days 1 to 28
Supportive medications
- Sargramostim (Leukine) 125 mcg/m2 SC once per day on days 1 to 14
28-day cycles, alternating with pulse cycles:
Immunotherapy, pulse cycles (2, 3, 5, 6, 8, 10, 12)
- IL-2 - Aldesleukin (Proleukin) 18,000,000 units/m2 IV continuous infusion over 6 hours, 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
- Sargramostim (Leukine) 125 mcg/m2 SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)
- Ondansetron (Zofran) 32 mg IV or Granisetron 2 mg IV once per day
- Omeprazole (Prilosec) 20 mg PO QPM
- Acetaminophen (Tylenol) 650 mg PO every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
- Meperidine (Demerol) 25 mg IV every 6 hours as needed for chills and rigors
28-day cycles, alternating with low-dose cycles, for a total of 12 cycles
References
- O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. link to original article contains verified protocol PubMed
Ipilimumab monotherapy
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Regimen
Study | 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
- O'Day et al. 2010 and Margolin et al. 2012: Ipilimumab induction x 4
- CA184-024: Dacarbazine & Ipilimumab
Immunotherapy
- Ipilimumab (Yervoy) 10 mg/kg IV once on day 1
12-week cycles
References
- 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
- 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
- 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
- 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
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1, given second
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first
12-week cycle for 8 cycles
References
- CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed
- 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 (MCC-15400) | Phase I |
Note: it is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.
Preceding treatment
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
12-week cycle for 8 cycles (2 years)
References
- 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. link to original article contains verified protocol link to PMC article PubMed
- CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains protocol link to PMC article PubMed