Melanoma

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Elizabeth Buchbinder, MD
Dana-Farber Cancer Institute
Boston, MA

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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:

38 regimens on this page
71 variants on this page

Contents


Guidelines

EDF/EADO/EORTC

ESMO

Older

INMC

NCCN

Neoadjuvant response criteria

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 Years of enrollment Evidence Comparator Comparative Efficacy
Flaherty et al. 2014 (SWOG S0008) 2000-2007 Phase III (E-esc) IFN alfa-2b Seems to have superior RFS

Preceding treatment

Chemotherapy

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

  1. SWOG S0008: Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK; CALGB; COG; ECOG; SWOG. 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 NCT00006237

Interferon alfa-2a monotherapy

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Regimen variant #1, 12 months

Study Years of enrollment Evidence Comparator Comparative Efficacy
Pehamberger et al. 1998 1990-1994 Phase III (E-esc) 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)

Regimen variant #2, 18 months

Study Years of enrollment Evidence Comparator Comparative Efficacy
Grob et al. 1998 1990-NR Phase III (E-esc) Observation Might have superior OS
Hauschild et al. 2010 2001-2004 Phase III (C) IFN alfa-2a x 5 y Did not meet primary endpoint of RFS60

Preceding treatment

Immunotherapy

7-day cycle for 78 cycles (18 months)

Regimen variant #3, 24 months

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Garbe et al. 2008 1997-2001 Phase III (E-esc) 1. Dacarbazine & IFN alfa-2a Not reported
2. Observation Superior OS
Eigentler et al. 2016 (ML17840) 2004-2007 Phase III (C) Peginterferon alfa-2a Did not meet primary endpoint of DMFS Superior toxicity

Preceding treatment

Immunotherapy

7-day cycle for 104 cycles (2 years)

References

  1. Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K; Austrian Malignant Melanoma Cooperative Group. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. 1998 Apr;16(4):1425-9. link to original article contains verified protocol PubMed
  2. Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ; French Cooperative Group on Melanoma. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet. 1998 Jun 27;351(9120):1905-10. link to original article contains verified protocol PubMed
  3. Garbe C, Radny P, Linse R, Dummer R, Gutzmer R, Ulrich J, Stadler R, Weichenthal M, Eigentler T, Ellwanger U, Hauschild A; DeCOG. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol. 2008 Jun;19(6):1195-201. Epub 2008 Feb 14. link to original article contains protocol PubMed
  4. Hauschild A, Weichenthal M, Rass K, Linse R, Berking C, Böttjer J, Vogt T, Spieth K, Eigentler T, Brockmeyer NH, Stein A, Näher H, Schadendorf D, Mohr P, Kaatz M, Tronnier M, Hein R, Schuler G, Egberts F, Garbe C. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol. 2010 Feb 10;28(5):841-6. Epub 2010 Jan 4. link to original article contains protocol PubMed
  5. ML17840: Eigentler TK, Gutzmer R, Hauschild A, Heinzerling L, Schadendorf D, Nashan D, Hölzle E, Kiecker F, Becker J, Sunderkötter C, Moll I, Richtig E, Pönitzsch I, Pehamberger H, Kaufmann R, Pföhler C, Vogt T, Berking C, Praxmarer M, Garbe C; Dermatologic Cooperative Oncology Group. 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 NCT00204529

Interferon alfa-2b monotherapy

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HDI: High-Dose Interferon

Example orders

Regimen variant #1, 3M, 6-month course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cameron et al. 2001 (The Scottish study) NR Phase III (E-esc) Observation Did not meet primary endpoint of RFS

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

Preceding treatment

Immunotherapy

6-month course

Regimen variant #2, 3M, 18-month course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Grob et al. 2012 (EADO 2001/CMII) 2003-2005 Phase III (C) Peginterferon x 36 mo Did not meet primary endpoint of DFS60

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

Preceding treatment

Immunotherapy

18-month course

Regimen variant #3, 10M/5M, 24-month course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2005 (EORTC 18952) 1996-2000 Phase III (E-esc) 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

Regimen variant #4, 10M/10M, 12-month course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2005 (EORTC 18952) 1996-2000 Phase III (E-esc) 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

Regimen variant #5, 15M, 4-week course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Pectasides et al. 2009 1998-2004 Phase III (E-de-esc) Interferon alfa-2b; 15M/10M x 12 mo Non-inferior RFS

Preceding treatment

Immunotherapy

4-week course

Regimen variant #6, 20M, 4-week course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Agarwala et al. 2017 (ECOG-ACRIN E1697) 1998-NR Phase III (E-esc) Observation Did not meet primary endpoint of RFS

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

Preceding treatment

Immunotherapy

4-week course

Regimen variant #7, 20M/10M, 12-month course

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kirkwood et al. 1996 (ECOG E1684) 1984-1990 Phase III (E-RT-esc) Observation Seems to have superior OS
Kirkwood et al. 2000 (ECOG E1690) 1991-1995 Phase III (E-RT-esc) Observation Seems to have superior RFS
2. Interferon alfa-2b; low-dose x 24 mo Not directly compared
Kirkwood et al. 2001 (ECOG E1694) 1996-1999 Phase III (C) GM2-KLH/QS-21 vaccine Superior OS
McMasters et al. 2016 (Sunbelt) 1997-2003 Phase III (E-esc) Observation Did not meet primary endpoints of DFS/OS
Flaherty et al. 2014 (SWOG S0008) 2000-2007 Phase III (C) Biochemotherapy Seems to have inferior RFS
Mohr et al. 2015 (DeCOG MM-ADJ-5) 2003-2009 Phase III (C) Intermittent HDI Did not meet primary endpoint of DMFS
Tarhini et al. 2019 (ECOG E1609) 2011-2014 Phase III (C) Ipilimumab; 3 mg/kg Seems to have inferior OS
Ipilimumab; 10 mg/kg Did not meet primary endpoint of OS

Preceding treatment

Immunotherapy

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

12-month course

References

  1. ECOG E1684: Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7-17. link to original article contains verified protocol PubMed
  2. ECOG E1690: Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000 Jun;18(12):2444-58. link to original article PubMed
  3. ECOG E1694: Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, Rao U. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001 May 1;19(9):2370-80. link to original article contains verified protocol PubMed
  4. The Scottish Study: Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF; Scottish Melanoma Group. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001 May 4;84(9):1146-9. link to original article contains verified protocol link to PMC article PubMed
  5. EORTC 18952: Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. link to original article PubMed
    1. Update: Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G, Testori A; EORTC Melanoma Group. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016 Mar;55:111-21. link to original article PubMed
  6. Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, Kalofonos H, Fountzilas G, Panagiotou P, Kokkalis G, Papadopoulos O, Castana O, Papadopoulos S, Stavrinidis E, Vourli G, Ioannovich J, Gogas H. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol. 2009 Feb 20;27(6):939-44. Epub 2009 Jan 12. link to original article contains protocol PubMed
  7. EADO 2001/CMII: Grob JJ, Jouary T, Dréno B, Asselineau J, Gutzmer R, Hauschild A, Leccia MT, Landthaler M, Garbe C, Sassolas B, Herbst RA, Guillot B, Chene G, Pehamberger H. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study. Eur J Cancer. 2013 Jan;49(1):166-74. Epub 2012 Sep 10. link to original article contains protocol PubMed NCT00221702
  8. SWOG S0008: Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK; SWOG; CALGB; COG; ECOG. 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 NCT00006237
  9. DeCOG MM-ADJ-5: Mohr P, Hauschild A, Trefzer U, Enk A, Tilgen W, Loquai C, Gogas H, Haalck T, Koller J, Dummer R, Gutzmer R, Brockmeyer N, Hölzle E, Sunderkötter C, Mauch C, Stein A, Schneider LA, Podda M, Göppner D, Schadendorf D, Weichenthal M. Intermittent high-dose intravenous interferon alfa-2b for adjuvant treatment of stage III melanoma: final analysis of a randomized phase III Dermatologic Cooperative Oncology Group trial. J Clin Oncol. 2015 Dec 1;33(34):4077-84. Epub 2015 Oct 26. link to original article contains verified protocol PubMed NCT00226408
  10. Sunbelt: McMasters KM, Egger ME, Edwards MJ, Ross MI, Reintgen DS, Noyes RD, Martin RC 2nd, Goydos JS, Beitsch PD, Urist MM, Ariyan S, Sussman JJ, Davidson BS, Gershenwald JE, Hagendoorn LJ, Stromberg AJ, Scoggins CR. Final results of the Sunbelt melanoma trial: a multi-institutional prospective randomized phase III study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J Clin Oncol. 2016 Apr 1;34(10):1079-86. Epub 2016 Feb 8. link to original article link to PMC article contains verified protocol PubMed
  11. ECOG-ACRIN E1697: Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III randomized study of 4 weeks of high-dose interferon-α-2b in stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article contains verified protocol PubMed NCT00003641
  12. ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains verified protocol PubMed

Ipilimumab monotherapy

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Example orders

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Tarhini et al. 2019 (ECOG E1609) 2011-2014 Phase III (E-switch-ic) Interferon alfa-2b Seems to have superior OS
Ipilimumab; 10 mg/kg Not reported

Preceding treatment

Immunotherapy

3-week cycle for 4 cycles, then 12-week cycle for up to 4 cycles

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

Study Years of enrollment Evidence Comparator Comparative Efficacy 12-month recurrence-free survival (RFS) Comparator RFS
Tarhini et al. 2019 (ECOG E1609) 2011-2014 Phase III (E-switch-ic) Interferon alfa-2b Did not meet primary endpoint of OS
Ipilimumab; 3 mg/kg Not reported
Weber et al. 2017 (Checkmate 238) 2015 Phase III (C) Nivolumab Inferior RFS 61% overall
Stage IIIB or IIIC: 62% (95% CI: 56-66.5)
Stage IV: 57.5% (95% CI: 46-67)
70.5% overall
Stage IIIB or IIIC: 72% (95% CI, 67-77)
Stage IV: 63% (95% CI, 52-72.5)

Preceding treatment

Immunotherapy

3-week cycle for 4 cycles, then 12-week cycle for up to 4 cycles

Regimen variant #3, 3 years

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Eggermont et al. 2015 (EORTC 18071) 2008-2011 Phase III (E-RT-esc) Placebo Superior OS (*) Similar HRQoL

Note: Reported efficacy 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

Immunotherapy

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

References

  1. EORTC 18071: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. link to original article contains verified protocol PubMed
    1. Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
    2. HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to PMC article PubMed
  2. CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA1; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed
  3. ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy 12-month recurrence-free survival (RFS) Comparator RFS
Weber et al. 2017 (Checkmate 238) 2015 Phase III (E-RT-switch-ic) Ipilimumab Superior RFS 70.5% overall
Stage IIIB or IIIC: 72.3% (95% CI, 67.4 to 76.7)
Stage IV: 63.0% (95% CI, 51.6 to 72.5)
60.8% overall
Stage IIIB or IIIC: 61.6% (95% CI, 56.3 to 66.5)
Stage IV: 57.5% (95% CI, 46.0 to 67.4)

Preceding treatment

Immunotherapy

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

References

  1. CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA1; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed

Peginterferon alfa-2b monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2008 (EORTC 18991) 2000-2003 Phase III (E-RT-esc) 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

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

Pembrolizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2018 (EORTC 1325/KEYNOTE-054) 2015-2016 Phase III (E-RT-esc) Placebo Superior RFS

Preceding treatment

Immunotherapy

21-day cycle for 18 cycles

References

  1. EORTC 1325/KEYNOTE-054: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains verified protocol PubMed NCT02362594

Local therapy

Talimogene laherparepvec monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Andtbacka et al. 2015 (OPTiM) 2009-2011 Phase III (E-switch-ooc) 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

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

Metastatic or unresectable disease

ABC

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

Regimen

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

The doses listed here are the amended starting doses.

Chemotherapy

28-day cycles

References

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

Carboplatin & Paclitaxel

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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, AUC 2/100

Study Evidence
Rao et al. 2006 Retrospective

Chemotherapy

28-day cycles

Regimen variant #2, AUC 6/175

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

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

Chemotherapy

21-day cycles

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hauschild et al. 2009 (Bayer 11718) 2005-2006 Phase III (C) CP & Sorafenib Did not meet primary endpoint of PFS
Flaherty et al. 2013 (ECOG E2603) 2005-2008 Phase III (C) CP & Sorafenib Did not meet primary endpoint of OS

Chemotherapy

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

21-day cycle for up to 10 cycles

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

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

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

Chemotherapy

8-week cycles

References

  1. Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. link to original article contains protocol PubMed
  2. Retrospective: Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article PubMed
  3. Bayer 11718: Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. link to original article contains verified protocol PubMed NCT00111007
  4. ECOG E2603: Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. link to original article contains verified protocol link to PMC article PubMed NCT00110019
  5. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article contains protocol PubMed
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed

Carboplatin & nab-Paclitaxel

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Regimen

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

Chemotherapy

Supportive medications

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

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

References

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

Cisplatin & Dacarbazine

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Regimen

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

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

Chemotherapy

21-day cycle for 6 cycles

References

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

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

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ridolfi et al. 2002 1997-1999 Phase III (E-esc) Cisplatin, Dacarbazine +/- Carmustine Did not meet primary endpoint of OS

Chemotherapy

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

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

Cisplatin, Dacarbazine, Paclitaxel

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Regimen

Study Evidence
Papadopoulos et al. 2009 Phase I/II

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

Chemotherapy

Continued indefinitely

References

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

CVD (Vinblastine)

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CVD: Cisplatin, Vinblastine, Dacarbazine

Regimen variant #1, 20/1.2/800

Study Years of enrollment Evidence Comparator Comparative Efficacy
Atkins et al. 2008 (ECOG E3695) 1997-2002 Phase III (C) Sequential biochemotherapy Seems to have inferior PFS

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

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Regimen variant #2, 20/1.6/800

Study Evidence
Legha et al. 1989 Phase II

Chemotherapy

21-day cycles

Regimen variant #3, 20/2/800

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eton et al. 2002 1993-1999 Phase III (C) Sequential biochemotherapy Inferior TTP

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

Chemotherapy

21-day cycle for up to 10 cycles

References

  1. Legha SS, Ring S, Papadopoulos N, Plager C, Chawla S, Benjamin R. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer. 1989 Nov 15;64(10):2024-9. link to original contains protocol PubMed
  2. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. ECOG E3695: Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; ECOG. 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 Years of enrollment Evidence Comparator Comparative Efficacy
Jungnelius et al. 1998 NR Phase III (E-esc) Dacarbazine & Vindesine Superior TTP
Bajetta et al. 2006 1999-2003 Phase III (C) Biochemotherapy Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

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

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

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

Example orders

Regimen variant #1, 4 cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
McDermott et al. 2000 1996-1997 Phase II
Atkins et al. 2008 (ECOG E3695) 1997-2002 Phase III (E-esc) CVD Seems to have superior PFS

Chemotherapy

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

21-day cycle for up to 4 cycles

Regimen variant #2, 5 cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eton et al. 2002 1993-1999 Phase III (E-esc) CVD Superior TTP

Chemotherapy

Immunotherapy

42-day cycle for up to 5 cycles

Regimen variant #3, 6 cycles

Study Evidence
Legha et al. 1998 Phase II

Chemotherapy

Immunotherapy

21-day cycle for 6 cycles

References

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

Regimen variant #1, 850 mg/m2 q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Pritchard et al. 1980 NR in abstract Phase II
Robert et al. 2011 (CA184-024) 2006-2008 Phase III (C) Dacarbazine & Ipilimumab Inferior OS

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

Chemotherapy

21-day cycle for 8 cycles

Regimen variant #2, 850 mg/m2 q4wk

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

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

Chemotherapy

28-day cycles

Regimen variant #3, 900 mg/m2 q3wk

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

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

Chemotherapy

21-day cycles

Regimen variant #4, 1000 mg/m2 q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Chapman et al. 1999 1991-1997 Phase III (C) Dartmouth regimen Might have inferior ORR
Testori et al. 2008 (C-100-21) 2002-2004 Phase III (C) Vitespen Did not meet primary endpoint of OS
Bedikian et al. 2010 2002-2007 Phase III (C) DHA-paclitaxel Did not meet primary endpoint of OS
Patel et al. 2011 (EORTC 18032) 2004-2007 Phase III (C) Temozolomide Did not meet primary endpoint of OS
Ribas et al. 2013 (A3671009) 2006-2007 Phase III (C) Tremelimumab Did not meet primary endpoint of OS
Ugurel et al. 2017 (ChemoSensMM) 2008-2012 Phase III (C) Chemosensitivity-directed therapy Did not meet primary endpoint of OS
Hersh et al. 2015 2009-2011 Phase III (C) nab-Paclitaxel Seems to have inferior PFS
Weber et al. 2015 (CheckMate 037) 2012-2014 Phase III (C) Nivolumab Inferior ORR (*)
Robert et al. 2014 (CheckMate 066) 2013-2014 Phase III (C) Nivolumab Inferior OS

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

Chemotherapy

21-day cycles

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

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

Chemotherapy

28-day cycles

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cocconi et al. 1992 1983-1988 Phase III (C) Dacarbazine & Tamoxifen Seems to have inferior OS
Middleton et al. 2000b 1995-1997 Phase III (C) Temozolomide Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

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

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

Chemotherapy

28-day cycles

Regimen variant #8, 2500 mg/m2, split doses, q4wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Luikart et al. 1984 NR Phase III (C) VBD Did not meet efficacy endpoints

Chemotherapy

28-day cycles

References

  1. Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
  2. Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article contains verified protocol PubMed
  3. Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains verified protocol PubMed
  4. Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; ECOG. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. link to original article contains verified protocol PubMed
  5. Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. link to original article contains protocol PubMed
  6. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
  7. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains verified protocol PubMed
  8. Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. link to original article contains protocol PubMed
  9. 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
  10. 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
  11. 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 NCT00005052
  12. CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed NCT00324155
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
  13. A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains verified protocol link to PMC article PubMed NCT00257205
  14. SICOG 0109: Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. link to original article link to PMC article contains verified protocol PubMed NCT01359956
  15. CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains verified protocol PubMed
    1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
  16. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed
  17. Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains verified protocol link to PMC article PubMed
  18. ChemoSensMM: Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. [=18635 link to original article] link to PMC article contains verified protocol PubMed NCT00779714

Dacarbazine & Interferon alfa-2a

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Middleton et al. 2000a 1994-1998 Phase III (C) DBCT Did not meet primary efficacy endpoints
Hauschild et al. 2001 1994-1998 Phase III (C) Dacarbazine, IFN alfa, IL-2 Did not meet primary endpoint of OS

Note: in Hauschild et al. 2001, the interferon is described as "IFN-α2a/b" without further details.

Chemotherapy

Immunotherapy

References

  1. Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM, Harper P, Thatcher N. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer. 2000 Mar;82(6):1158-62. link to original article link to PMC article PubMed
  2. Hauschild A, Garbe C, Stolz W, Ellwanger U, Seiter S, Dummer R, Ugurel S, Sebastian G, Nashan D, Linse R, Achtelik W, Mohr P, Kaufmann R, Fey M, Ulrich J, Tilgen W; Dermatologic Cooperative Oncology Group. 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 Years of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (CA184-024) 2006-2008 Phase III (E-esc) Dacarbazine Superior OS

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment

References

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

Docetaxel monotherapy

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Regimen

Study Evidence
Aamdal et al. 1994 Phase II

Chemotherapy

Supportive medications

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

21-day cycles

References

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

Fotemustine monotherapy

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Regimen

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

Chemotherapy

  • Fotemustine (Muphoran) as follows:
    • Weeks 1 to 3: 100 mg/m2 IV once per day on days 1, 8, 15
    • Weeks 4 to 8: no treatment
    • Week 9 onwards: 100 mg/m2 IV once on day 1, every 3 weeks

8-week induction cycle, then 21-day cycles

References

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

High-dose Interleukin-2

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HD IL-2: High-Dose InterLeukin-2

Example orders

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 1993 NR Phase III (C) HD IL-2 & IFN alfa-2a Did not meet primary endpoint of OS50%
Rosenberg et al. 1994 1985-1992 Non-randomized
Atkins et al. 1999 1985-1993 Phase II (RT)
Schwartzentruber et al. 2011 (NCI-2012-02897) 2000-2007 Phase III (C) HD IL-2 & gp100 vaccine Seems to have inferior clinical response

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

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 600,000 or 720,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5
    • After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above

Supportive medications

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

References

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

Low-dose Interleukin-2

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LD IL-2: Low-Dose InterLeukin-2

Regimen

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

Immunotherapy

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

6-week cycles

References

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

Ipilimumab monotherapy

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Example orders

Regimen variant #1, 3 mg/kg

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hodi et al. 2010 (MDX010-20) NR-2008 Phase III (E-RT-switch-ooc) 1. Ipilimumab & gp100 peptide vaccine Did not meet primary endpoint of OS
2. gp100 peptide vaccine Superior OS
Ascierto et al. 2017 (CA184-169) 2012 Phase III (C) Ipilimumab; 10 mg/kg Seems to have inferior OS
Robert et al. 2015 (KEYNOTE-006) 2013-2014 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) 2013-2014 Phase III (C) Ipilimumab & Nivolumab Inferior PFS
Larkin et al. 2015 (CheckMate 067) 2013-2014 Phase III (C) 1. Ipilimumab & Nivolumab Inferior OS (*) Equivalent HRQoL
2. Nivolumab Inferior OS (*) Equivalent HRQoL

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

Immunotherapy

21-day cycle for 4 cycles

Regimen variant #2, 10 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2008 2003-2005 Phase I/II
Wolchok et al. 2010 (CA184-022) 2006-2007 Phase II
O'Day et al. 2010 (CA184-008) 2006-2007 Phase II
Margolin et al. 2012 (CA184-042) 2008-2009 Phase II
Hodi et al. 2014 (ECOG E1608) 2010-2011 Randomized Phase II (C) Ipilimumab & Sargramostim Inferior OS
Ascierto et al. 2017 (CA184-169) 2012 Phase III (C) Ipilimumab; 3 mg/kg Seems to have superior OS

Note: In CA184-022, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. link to original article PubMed
  2. CA184-022: Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. link to original article contains verified protocol PubMed NCT00289640
  3. MDX010-20: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains verified protocol link to PMC article PubMed NCT00094653
    1. Update: McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. link to original article PubMed
  4. CA184-008: O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains verified protocol PubMed NCT00289627
  5. CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains protocol PubMed NCT00623766
  6. ECOG E1608: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. link to original article link to PMC article contains protocol PubMed NCT01134614
  7. KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains verified protocol PubMed NCT01866319
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
    2. Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
  8. CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed NCT01927419
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
  9. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
    2. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
    3. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
  10. CA184-169: Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. link to original article PubMed NCT01515189

Ipilimumab & Nivolumab

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Larkin et al. 2015 (CheckMate 067) 2013-2014 Phase III (E-RT-esc) 1. Ipilimumab Superior OS (*) Equivalent HRQoL
2. Nivolumab Superior PFS Equivalent HRQoL

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

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

  • Nivolumab (Opdivo) 3 mg/kg IV once on day 1
    • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wolchok et al. 2013 (CA209-004) 2009-2013 Phase 1
Postow et al. 2015 (CheckMate 069) 2013-2014 Phase III (E-esc) Ipilimumab Superior PFS

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

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

21-day cycle for 4 cycles

Subsequent treatment

References

  1. Phase I: Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. link to original article contains verified protocol link to supplementary appendix PubMed NCT01024231
  2. CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed NCT01927419
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
  3. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
    2. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
    3. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed

Ipilimumab, then Nivolumab

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Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2016 (CheckMate 064) 2013-2014 Randomized Phase II (E-switch-ic) Nivolumab, then Ipilimumab Seems to have inferior OS

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

  • Nivolumab (Opdivo) 3 mg/kg IV once on day 1
    • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycle for 6 cycles

Subsequent treatment

References

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

Nivolumab monotherapy

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Regimen variant #1, limited duration

Study Evidence
Weber et al. 2013 (MCC-15400) Phase I

Immunotherapy

  • Nivolumab (Opdivo) 3 mg/kg IV once on day 1
    • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycle for 12 cycles

Subsequent treatment

Regimen variant #2, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Weber et al. 2015 (CheckMate 037) 2012-2014 Phase III (E-RT-switch-ooc) 1. Dacarbazine
2. Carboplatin & Paclitaxel
Superior ORR (*)
Robert et al. 2014 (CheckMate 066) 2013-2014 Phase III (E-RT-switch-ooc) Dacarbazine Superior OS
Larkin et al. 2015 (CheckMate 067) 2013-2014 Phase III (E-RT-switch-ic) 1. Ipilimumab Superior OS (*) Equivalent HRQoL
2. Ipilimumab & Nivolumab Inferior PFS Equivalent HRQoL

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

Immunotherapy

  • Nivolumab (Opdivo) 3 mg/kg IV once on day 1
    • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

References

  1. Phase I: Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. contains verified protocol link to PMC article PubMed
  2. CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains verified protocol PubMed
    1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
  3. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article PubMed
  4. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed
    2. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
    3. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed

Nivolumab, then Ipilimumab

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Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2016 (CheckMate 064) 2013-2014 Randomized Phase II (E-switch-ic) Ipilimumab, then Nivolumab Seems to have superior OS

Immunotherapy, part 1

  • Nivolumab (Opdivo) 3 mg/kg IV once on day 1
    • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycle for 6 cycles, followed by:

Immunotherapy, part 2

21-day cycle for 4 cycles

Subsequent treatment

References

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

Paclitaxel monotherapy

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Example orders

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

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

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

Chemotherapy

28-day cycles

Regimen variant #2, 250 mg/m2 q3wk

Study Evidence
Legha et al. 1990 Phase II

Chemotherapy

21-day cycles

References

  1. Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. link to original article contains protocol PubMed
  2. SYMMETRY: O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. link to original article contains verified protocol PubMed NCT00522834
  3. SUMMIT-1: Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. link to original article contains verified protocol PubMed NCT01006252

nab-Paclitaxel monotherapy

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hersh et al. 2012 NR Phase II
Hersh et al. 2015 2009-2011 Phase III (E-switch-ic) Dacarbazine Seems to have superior PFS

Chemotherapy

28-day cycles

Regimen variant #2

Study Evidence
Hersh et al. 2012 Phase II

Note: this dose was intended for previously treated patients.

Chemotherapy

28-day cycles

References

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

Pembrolizumab monotherapy

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Regimen variant #1, 2 mg/kg q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001) 2011-2012 Phase I, >20 pts
Ribas et al. 2015 (KEYNOTE-002) 2012-2013 Randomized Phase II (E-RT-switch-ooc) Investigator-choice of:
1. Carboplatin & Paclitaxel
2. Dacarbazine
3. Paclitaxel
4. Temozolomide
Superior PFS
5. Pembrolizumab; 10 mg/kg q3wk Did not meet primary endpoint of PFS

Immunotherapy

21-day cycles

Regimen variant #2, 10 mg/kg q2wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001) 2011-2012 Phase I, >20 pts
Robert et al. 2015 (KEYNOTE-006) 2013-2014 Phase III (E-RT-switch-ic) 1. Ipilimumab Superior OS
2. Pembrolizumab; 10 mg/kg q3wk Did not meet primary endpoints of PFS/OS

Immunotherapy

14-day cycles

Regimen variant #3, 10 mg/kg q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001) 2011-2012 Phase I, >20 pts
Ribas et al. 2015 (KEYNOTE-002) 2012-2013 Randomized Phase II (E-RT-switch-ooc) Investigator-choice of:
1. Carboplatin & Paclitaxel
2. Dacarbazine
3. Paclitaxel
4. Temozolomide
Superior PFS
5. Pembrolizumab; 2 mg/kg Did not meet primary endpoint of PFS
Robert et al. 2015 (KEYNOTE-006) 2013-2014 Phase III (E-RT-switch-ic) 1. Ipilimumab Superior OS
2. Pembrolizumab; 10 mg/kg q2wk Did not meet primary endpoints of PFS/OS

Immunotherapy

21-day cycles

Regimen variant #4, 200 mg q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Long et al. 2019 (ECHO-301/KEYNOTE-252) 2016-2017 Phase III (C) Epacadostat & Pembrolizumab Did not meet primary endpoints of PFS/OS

Immunotherapy

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

References

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

Temozolomide monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Middleton et al. 2000b 1995-1997 Phase III (E-switch-ic) Dacarbazine Did not meet primary endpoint of OS
Kaufmann et al. 2005 1998-2001 Phase III (C) Temozolomide & Interferon-alfa Seems to have inferior ORR
Ribas et al. 2013 (A3671009) 2006-2007 Phase III (C) Tremelimumab Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

References

  1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
  2. 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
  3. A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains verified protocol link to PMC article PubMed NCT00257205

Temozolomide & Bevacizumab

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TB: Temozolomide & Bevacizumab

Regimen

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

Chemotherapy

28-day cycles

References

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

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)

Supportive medications

28-day cycles, alternating with pulse cycles:

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

  • IL-2 - Aldesleukin (Proleukin) 18,000,000 units/m2 IV continuous infusion over 6 hours, then 18,000,000 units/m2 IV continuous infusion over 12 hours, then 18,000,000 units/m2 IV continuous infusion over 24 hours on days 1 to 2
    • Then as an outpatient: 1,000,000 units/m2 SC once per day every Monday to Friday on days 3 to 28

Supportive medications

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

References

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

Ipilimumab monotherapy

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Regimen

Study Evidence
O'Day et al. 2010 (CA184-008) Phase II
Robert et al. 2011 (CA184-024) Non-randomized portion of RCT
Margolin et al. 2012 (CA184-042) Phase II

Preceding treatment

Immunotherapy

12-week cycles

References

  1. CA184-008: O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains verified protocol PubMed NCT00289627
  2. CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed NCT00324155
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
  3. CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains protocol PubMed NCT00623766

Ipilimumab & Nivolumab

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Regimen

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

Preceding treatment

Immunotherapy

12-week cycle for 8 cycles

References

  1. CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed NCT01927419
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed

Nivolumab monotherapy

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Regimen 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

Regimen 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

  1. Phase I: Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. link to original article contains verified protocol link to PMC article PubMed
  2. CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains protocol link to PMC article PubMed NCT01783938