Melanoma

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

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: some melanoma regimens can be found on dedicated pages:

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

39 regimens on this page 75 variants on this page

Guidelines

EDF/EADO/EORTC

• 2016: Garbe et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016 PubMed

ESMO

• 2020: Keilholz et al. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee
• 2020: Michielin et al. ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee

Older

• 2019: Michielin et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2015: Dummer et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. PubMed

INMC

• 2019: Amaria et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium

NCCN

• NCCN Guidelines - Cutaneous Melanoma

Neoadjuvant response criteria

• 2018: Tetzlaff et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma

Adjuvant therapy

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

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

Example orders

• Example orders for CVD, IL-2, IFN alfa-2b - sequential biochemotherapy in melanoma

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

• Surgery

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 to 4, given first
• Vinblastine (Velban) 1.2 mg/m² IV push once per day on days 1 to 4, given second
• Dacarbazine (DTIC) 800 mg/m² IV over 60 minutes once on day 1, given third

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m²)
• Interferon alfa-2b (Intron-A) 5,000,000 units/m² SC once per day on days 1 to 5, 8, 10, 12
  • Doses on days 8, 10, 12 are given as outpatient doses

21-day cycle for 3 cycles

References

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

• Surgery

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

• Surgery

Immunotherapy

• Interferon alfa-2a (Roferon-A) 3,000,000 international units SC once per day on days 1, 3, 5

7-day cycle for 78 cycles (18 months)

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

• Surgery, within 3 months

Immunotherapy

• Interferon alfa-2a (Roferon-A) 3,000,000 international units SC once per day on days 1, 3, 5

7-day cycle for 104 cycles (2 years)

References

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

• Example orders for adjuvant Interferon alfa-2b (Intron-A) in melanoma

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

• Surgery

Immunotherapy

• Interferon alfa-2b (Intron-A) 3,000,000 units SC three times per week

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

• Surgery

Immunotherapy

• Interferon alfa-2b (Intron-A) 3,000,000 units SC three times per week

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

• Surgery

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

• Surgery

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

• Surgery

Immunotherapy

• Interferon alfa-2b (Intron-A) 15,000,000 units/m² IV five times per week

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

• Surgery

Immunotherapy

• Interferon alfa-2b (Intron-A) 20,000,000 units/m² IV five times per week

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

• Surgery

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

• Example orders for Ipilimumab (Yervoy) in melanoma

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

• Complete resection of stage IIIB, IIIC, or IV melanoma

Immunotherapy

• Ipilimumab (Yervoy) 3 mg/kg IV once on day 1

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

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	12-month recurrence-free survival (RFS)	Comparator RFS
Tarhini et al. 2019 (ECOG E1609)	2011-2014	Phase 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

• Complete resection of stage IIIB, IIIC, or IV melanoma

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

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

Regimen variant #3, 3 years

FDA-recommended dose

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

Note: Reported efficacy is based on the 2019 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

• Complete resection of stage III cutaneous melanoma

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1

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

References

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
   3. Update: Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. link to original article PubMed
2. CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed NCT02388906
   1. Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
3. ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains verified protocol PubMed

Ipilimumab & Nivolumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zimmer et al. 2020 (IMMUNED)	2015-2018	Randomized Phase II (E-esc)	1. Nivolumab	Not reported
			2. Placebo	Superior RFS

Preceding treatment

• Resection or radiotherapy of stage IV melanoma, with NED

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 1 to 4: 3 mg/kg IV once on day 1
• Nivolumab (Opdivo) as follows:
  • Cycles 1 to 4: 1 mg/kg IV once on day 1,
  • Cycles 5 to 24: 3 mg/kg IV once on day 1

21-day cycle for 4 cycles, then 14-day cycle for 20 cycles (1 year)

References

1. IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains verified protocol PubMed NCT02523313

Nivolumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	12-month recurrence-free survival (RFS)	Comparator RFS
Weber et al. 2017 (Checkmate 238)	2015	Phase III (E-RT-switch-ic)	Ipilimumab	Superior RFS	71% overall Stage IIIB or IIIC: 72.3% (95% CI, 67 to 77) Stage IV: 63.0% (95% CI, 52 to 73)	61% overall Stage IIIB or IIIC: 61.6% (95% CI, 56 to 66.5) Stage IV: 57.5% (95% CI, 46 to 67)
Zimmer et al. 2020 (IMMUNED)	2015-2018	Randomized Phase II (E-esc)	1. Ipilimumab & Nivolumab	Not reported
			2. Placebo	Seems to have superior RFS	52% (95% CI, 38 to 64)

Preceding treatment

• Checkmate 238: Complete resection of stage IIIB, IIIC, or IV melanoma
• IMMUNED: Resection or radiotherapy of stage IV melanoma, with NED

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

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

References

1. CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed NCT02388906
   1. Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
2. IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains verified protocol PubMed NCT02523313

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

• Surgery

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 NCT00006249
   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

• Complete regional lymphadenectomy, within 13 weeks

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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, first-line

Dacarbazine monotherapy

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Example orders

• Example orders for Dacarbazine (DTIC) in melanoma

Regimen variant #1, 850 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
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

• Dacarbazine (DTIC) 850 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen variant #2, 850 mg/m² q4wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schadendorf et al. 2006	2000-2003	Phase 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

• Dacarbazine (DTIC) 850 mg/m² IV once on day 1

28-day cycles

Regimen variant #3, 1000 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2014 (CheckMate 066)	2013-2014	Phase III (C)	Nivolumab	Inferior OS

Chemotherapy

• Dacarbazine (DTIC) 1000 mg/m² IV once on day 1

21-day cycles

References

1. 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
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. 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

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

• Dacarbazine (DTIC) as follows:
  • Cycles 1 to 8: 850 mg/m² IV once on day 1
• Ipilimumab (Yervoy) as follows:
  • Cycles 1 to 4: 10 mg/kg IV once on day 1
  • Cycle 9 onwards: 10 mg/kg IV once on day 1

21-day cycle for 8 cycles, then 12-week cycles

References

1. CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article 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

Ipilimumab monotherapy

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Example orders

• Example orders for Ipilimumab (Yervoy) in melanoma

Regimen variant #1, 3 mg/kg

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Larkin et al. 2015 (CheckMate 067)	2013-2014	Phase III (C)	1. Ipilimumab & Nivolumab	Inferior OS (*)	Equivalent HRQoL
			2. Nivolumab	Inferior OS (*)	Equivalent HRQoL
Postow et al. 2015 (CheckMate 069)	2013-2014	Phase III (C)	Ipilimumab & Nivolumab	Inferior PFS

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

Immunotherapy

• Ipilimumab (Yervoy) 3 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles

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 contains verified protocol 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
2. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed NCT01844505
   1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article 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 & 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. Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 1 to 4: 3 mg/kg IV once on day 1
• Nivolumab (Opdivo) as follows:
  • Cycles 1 to 4: 1 mg/kg IV once on day 1
  • Cycle 5 onwards: 3 mg/kg IV once on day 1

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

Regimen variant #2

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

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 1 to 4: 3 mg/kg IV once on day 1, given second
• Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first

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

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 contains verified protocol 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
2. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed NCT01844505
   1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article 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 monotherapy

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Regimen variant #1, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
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: 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. 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
2. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed NCT01844505
   1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article 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

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

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 80 mg/m² IV once per day on days 1, 8, 15
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
• Carboplatin (Paraplatin) AUC 5 IV once on day 1

28-day cycles

References

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 (CP)

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CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, AUC 2/100

Study	Evidence
Rao et al. 2006	Retrospective

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15
• Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, AUC 6/175

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

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

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

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

• Carboplatin (Paraplatin) 200 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36
• Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

8-week cycles

References

1. Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. link to original article 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

• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, given second
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

Supportive medications

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

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

References

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

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1

21-day cycle for 6 cycles

References

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

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1
• Optional: Carmustine (BCNU) 100 mg/m² (note: in Ridolfi et al. 2002, in contrast to the treatment text, figure 1 lists a dosage of 150 mg/m²) IV once on day 1

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 4,500,000 units/m² (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) SC once per day on days 3 to 5, 8 to 12
• Interferon alfa-2b (Intron-A) 3,000,000 units/m² (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) IM on days 3 to 5 of week 1, then 3 times per week on all later weeks

21-day cycle for 6 cycles

References

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

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1
• Paclitaxel (Taxol) 120 mg/m² IV once per day on days 1 & 8

Continued indefinitely

References

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

• Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 to 4, given first
• Vinblastine (Velban) 1.2 mg/m² IV push once per day on days 1 to 4, given second
• Dacarbazine (DTIC) 800 mg/m² IV over 60 minutes once on day 1, given third

Supportive medications

• Antiemetics
• Dexamethasone (Decadron)

21-day cycle for up to 4 cycles

Regimen variant #2, 20/1.6/800

Study	Evidence
Legha et al. 1989	Phase II

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 2 to 5
• Vinblastine (Velban) 1.6 mg/m² IV once per day on days 1 to 5
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1

21-day cycles

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

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4
• Vinblastine (Velban) 2 mg/m² IV once per day on days 1 to 4
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1

21-day cycle for up to 10 cycles

References

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

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1 to 3
• Vindesine (Eldisine) 2.5 mg/m² IV once on day 1
• Dacarbazine (DTIC) 250 mg/m² IV once per day on days 1 to 3

21-day cycles

References

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

• Example orders for CVD, IL-2, IFN alfa-2b - sequential biochemotherapy in melanoma

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

• Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 to 4, given first
• Vinblastine (Velban) 1.2 mg/m² IV push once per day on days 1 to 4, given second
• Dacarbazine (DTIC) 800 mg/m² IV over 60 minutes once on day 1, given third

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m²)
• Interferon alfa-2b (Intron-A) 5,000,000 units/m² SC once per day on days 1 to 5, 8, 10, 12
  • Doses on days 8, 10, 12 are given as outpatient doses

Supportive medications

• All antihypertensive therapy discontinued at least 24 hours before each cycle
• Cephalexin (Keflex) or Ciprofloxacin (Cipro) 250 mg PO twice per day on days 1 to 14
• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 16, or until ANC greater than 10,000/uL
• Ondansetron (Zofran) 32 mg IV once per day
• Lorazepam (Ativan) 1 mg IV or PO every 6 hours
• Acetaminophen (Tylenol) 650 mg PO every 6 hours
• Ranitidine (Zantac) 150 mg PO every 12 hours
• Hydroxyzine (Atarax) 25 to 50 mg PO or Diphenhydramine (Benadryl) 25 mg PO every 6 hours for pruritis
• Meperidine (Demerol) 25 to 50 mg IV every 3 hours for chills and rigors
• Antidiarrheals & anxiolytics as needed

21-day cycle for up to 4 cycles

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

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4, 22 to 25
• Vinblastine (Velban) 1.5 mg/m² IV once per day on days 1 to 4, 22 to 25
• Dacarbazine (DTIC) 800 mg/m² IV once per day on days 1 & 22

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m²/day IV continuous infusion over 96 hours, started on days 5, 17, 26 (total dose per cycle: 108,000,000 units/m²)
• Interferon alfa-2b (Intron-A) 5,000,000 units/m² SC once per day on days 5 to 9, 17 to 21, 26 to 30

42-day cycle for up to 5 cycles

Regimen variant #3, 6 cycles

Study	Evidence
Legha et al. 1998	Phase II

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4
• Vinblastine (Velban) 1.6 mg/m² IV once per day on days 1 to 4
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m²)
• Interferon alfa-2b (Intron-A) 5,000,000 units/m² SC once per day on days 1 to 5

21-day cycle for 6 cycles

References

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

• Example orders for Dacarbazine (DTIC) in melanoma

Regimen variant #1, 850 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pritchard et al. 1980	NR in abstract	Phase II

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

Chemotherapy

• Dacarbazine (DTIC) 850 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen variant #3, 900 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Daponte et al. 2013 (SICOG 0109)	2002-2007	Phase 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

• Dacarbazine (DTIC) 900 mg/m² IV once on day 1

21-day cycles

Regimen variant #4, 1000 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chapman et al. 1999	1991-1997	Phase 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 (*)

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

Chemotherapy

• Dacarbazine (DTIC) 1000 mg/m² IV once on day 1

21-day cycles

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

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

Chemotherapy

• Dacarbazine (DTIC) 200 mg/m² IV once per day on days 1 to 5

28-day cycles

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

• Dacarbazine (DTIC) 250 mg/m² IV over 20 to 30 minutes once per day on days 1 to 5

21-day cycles

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

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

Chemotherapy

• Dacarbazine (DTIC) 250 mg/m² IV over 20 to 30 minutes once per day on days 1 to 5

28-day cycles

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

• Dacarbazine (DTIC) 250 mg/m² IV once per day on days 1 to 10

28-day cycles

References

1. Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
2. Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article 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. 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
9. Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. link to original article link to PMC article contains protocol PubMed
10. EORTC 18032: Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; EORTC Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. link to original article contains protocol PubMed NCT00005052
11. 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
12. 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
13. 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
14. 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
15. 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

• Dacarbazine (DTIC)

Immunotherapy

• Interferon alfa-2a (Roferon-A)

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

Docetaxel monotherapy

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Regimen

Study	Evidence
Aamdal et al. 1994	Phase II

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

Supportive medications

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

21-day cycles

References

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

• Example orders for High-dose (HD) IL-2 in melanoma

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

• Included:
• Acetaminophen (Tylenol)
• Indomethacin (Indocin)
• Meperidine (Demerol)
• Ranitidine (Zantac)
• Cimetidine (Tagamet)
• Hydroxyzine (Atarax)
• Diphenhydramine (Benadryl)
• Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

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

References

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Agarwala et al. 2002	1997-1999	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

• Example orders for Ipilimumab (Yervoy) in melanoma

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

Immunotherapy

• Ipilimumab (Yervoy) 3 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles

Regimen variant #2, 10 mg/kg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2008	2003-2005	Phase 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

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• CA184-008 & CA184-042: Patients who were clinically stable could proceed to ipilimumab maintenance

References

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. 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
Wolchok et al. 2013 (CheckMate-004)	2009-2013	Phase 1

These doses were from the cohort deemed by CheckMate-004 as being "the maximum doses that were associated with an acceptable level of adverse events."

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 1 to 4: 3 mg/kg IV once on day 1, given second
• Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first

21-day cycle for 8 cycles

Subsequent treatment

• Ipilimumab & nivolumab maintenance

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

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

• Ipilimumab (Yervoy) 3 mg/kg IV once on day 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

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

14-day cycle for 6 cycles

Subsequent treatment

• Nivolumab maintenance

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

• Nivolumab maintenance

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 (*)

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

Immunotherapy

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

14-day cycles

References

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 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

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

• Ipilimumab (Yervoy) 3 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Nivolumab maintenance

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

• Example orders for Paclitaxel (Taxol) in melanoma

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

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 250 mg/m² q3wk

Study	Evidence
Legha et al. 1990	Phase II

Chemotherapy

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

21-day cycles

References

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

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2

Study	Evidence
Hersh et al. 2012	Phase II

Note: this dose was intended for previously treated patients.

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

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

• Pembrolizumab (Keytruda) 2 mg/kg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #2, 10 mg/kg q2wk

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

Immunotherapy

• Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1

14-day cycles

Regimen variant #3, 10 mg/kg q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001)	2011-2012	Phase I, >20 pts
Ribas et al. 2015 (KEYNOTE-002)	2012-2013	Randomized Phase 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

• Pembrolizumab (Keytruda) 10 mg/kg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #4, 200 mg q3wk

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

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg/kg IV once on day 1

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

• Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5, taken while fasting

28-day cycles

References

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

• Temozolomide (Temodar) 200 mg/m² PO once per day on days 1 to 5
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

28-day cycles

References

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

• Example orders for IL-2 maintenance biotherapy in melanoma

Regimen

Study	Evidence
O'Day et al. 2002	Phase II

Preceding treatment

• Induction biochemotherapy

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

• IL-2 - Aldesleukin (Proleukin) 1,000,000 units/m² SC once per day every Monday to Friday on days 1 to 28

Supportive medications

• Sargramostim (Leukine) 125 mcg/m² SC once per day on days 1 to 14

28-day cycles, alternating with pulse cycles:

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

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

Supportive medications

• Sargramostim (Leukine) 125 mcg/m² SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)
• Ondansetron (Zofran) 32 mg IV or Granisetron 2 mg IV once per day
• Omeprazole (Prilosec) 20 mg PO QPM
• Acetaminophen (Tylenol) 650 mg PO every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
• Meperidine (Demerol) 25 mg IV every 6 hours as needed for chills and rigors

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

References

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
Margolin et al. 2012 (CA184-042)	Phase II

Preceding treatment

• CA184-008 and CA184-042: Ipilimumab induction x 4

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV once on day 1

12-week cycles

References

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. CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains protocol PubMed NCT00623766

Nivolumab monotherapy

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Regimen variant #1, indefinite

Study	Evidence
Weber et al. 2016 (CheckMate 064)	Non-randomized portion of RCT

Preceding treatment

• Nivolumab, then Ipilimumab induction versus Ipilimumab, then Nivolumab induction

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

• Nivolumab induction

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