Melanoma

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Note: biomarker-specific regimens have been moved to dedicated pages:

34 regimens on this page
53 variants on this page

Contents


Guidelines

ESMO

NCCN

Adjuvant therapy

Interferon alfa-2a monotherapy

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Regimen #1

Study Evidence Comparator Efficacy
Grob et al. 1998 Phase III Observation Might have superior OS

Immunotherapy

18-month course

Regimen #2

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

Immunotherapy

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

12-month course

References

  1. Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. 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. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet. 1998 Jun 27;351(9120):1905-10. link to original article contains verified protocol PubMed

Interferon alfa-2b monotherapy

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Example orders

Regimen #1, 12-month course

Study Evidence Comparator Efficacy
Kirkwood et al. 1996 (ECOG EST 1684) Phase III Observation Seems to have superior OS

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

Regimen #2, 6-month course

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

Note: The PubMed version of Cameron et al. 2001's abstract says that interferon alfa-2b is given "twice weekly," in contrast to what the actual paper says, "thrice weekly."

Immunotherapy

6-month course

References

  1. 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. 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
  3. 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 SD article PubMed
  4. Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK. Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8. Epub 2014 Oct 20. link to PMC article PubMed
  5. Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article PubMed

Ipilimumab monotherapy

Source: Ipilimumab (Yervoy) for melanoma, adjuvant

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Example orders

Regimen #1, 3 years

Study Evidence Comparator Efficacy Toxicity
Eggermont et al. 2015 (EORTC 18071) Phase III Placebo Superior OS (*) Similar HRQoL

Treatment preceded by complete resection of stage III cutaneous melanoma. Efficacy is based on the 2016 update. While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinically relevance.

Immunotherapy

36-month course, unless disease recurrence or unacceptable toxicity

Regimen #2, 1 year

Study Evidence 12-month recurrence-free survival (RFS) Comparator Comparator RFS Pt Population Efficacy
Weber et al. 2017 (Checkmate 238) Phase III 61% overall
Stage IIIB or IIIC: 62% (95% CI: 56-66.5)
Stage IV: 57.5% (95% CI: 46-67)
Nivolumab 70.5% overall
Stage IIIB or IIIC: 72% (95% CI, 67-77)
Stage IV: 63% (95% CI, 52-72.5)
Stage IIIB, IIIC, or IV melanoma, metastases to regional lymph nodes or distant metastases that had been surgically resected. Inferior RFS

Immunotherapy

12-month course, unless disease recurrence or unacceptable toxicity

References

  1. 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. link to original article contains verified protocol PubMed
    1. Correction: Eggermont AM, Chiarion-Sileni V, Grob JJ. Correction to Lancet Oncol 2015; 16: 522-30. 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 Jun;16(6):e262. Epub 2015 May 27. link to correction PubMed
    2. 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
    3. HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to PMC article PubMed
  2. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA1; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains verified protocol PubMed

Nivolumab monotherapy

Source: Nivolumab (Opdivo) for melanoma, adjuvant

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Regimen

Study Evidence 12-month recurrence-free survival (RFS) Comparator Comparator RFS Pt Population Efficacy
Weber et al. 2017 (Checkmate 238) Phase III 70.5% overall
Stage IIIB or IIIC: 72.3% (95% CI, 67.4 to 76.7)
Stage IV: 63.0% (95% CI, 51.6 to 72.5)
Ipilimumab 60.8% overall
Stage IIIB or IIIC: 61.6% (95% CI, 56.3 to 66.5)
Stage IV: 57.5% (95% CI, 46.0 to 67.4)
Stage IIIB, IIIC, or IV melanoma, metastases to regional lymph nodes or distant metastases that had been surgically resected. Superior RFS

Immunotherapy

14-day cycles, given for up to 1 year, until disease recurrence, or unacceptable toxicity

References

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

Peginterferon alfa-2b monotherapy

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Regimen

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

Patients enrolled in EORTC 18991 had resected stage III melanoma.

Immunotherapy

Given for up to 5 years of therapy if ECOG performance status remained 0 or 1

References

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

Placebo (Observation)

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Regimen

Study Evidence Comparator Efficacy Toxicity
Kirkwood et al. 1996 (ECOG EST 1684) Phase III Interferon alfa-2b Seems to have inferior OS
Pehamberger et al. 1998 Phase III Interferon alfa-2a Seems to have inferior DFS
Grob et al. 1998 Phase III Interferon alfa-2a Might have inferior OS
Cameron et al. 2001 (The Scottish study) Phase III Interferon alfa-2b Seems not superior
Eggermont et al. 2008 (EORTC 18991) Phase III Pegylated interferon alfa-2b Seems to have inferior RFS
Eggermont et al. 2015 (EORTC 18071) Phase III Ipilimumab Inferior OS (*) Similar HRQoL
Agarwala et al. 2017 (ECOG E1697) Phase III Interferon alfa-2b Seems not superior

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

Treatment

References

  1. 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. Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol. 1998 Apr;16(4):1425-9. link to original article contains verified protocol PubMed
  3. 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. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet. 1998 Jun 27;351(9120):1905-10. link to original article contains verified protocol PubMed
  4. 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. 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 SD article PubMed
  6. Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-26. link to original article contains verified protocol PubMed
    1. Update: Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. Epub 2012 Sep 24. link to original article contains verified protocol PubMed
  7. 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. link to original article contains verified protocol PubMed
    1. Correction: Eggermont AM, Chiarion-Sileni V, Grob JJ. Correction to Lancet Oncol 2015; 16: 522-30. 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 Jun;16(6):e262. Epub 2015 May 27. link to correction PubMed
    2. 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
    3. 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
  8. Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article PubMed

Local therapy

Talimogene laherparepvec monotherapy

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Regimen

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

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

Therapy

  • Talimogene laherparepvec (Imlygic) as follows:
    • Initially: 106 pfu/mL (to seroconvert HSV-seronegative patients) SC intralesional injection once on day 1, then 108 pfu/mL SC intralesional injection once on day 22
    • Thereafter: 108 pfu/mL SC intralesional injection once every 2 weeks.
    • Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."

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

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

References

  1. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. link to original article contains verified protocol PubMed

Metastatic or unresectable disease

ABC

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

Regimen

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

The doses listed here are the amended starting doses.

Chemotherapy

28-day cycles, given until progression of disease

References

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

Carboplatin & Paclitaxel

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CP: Carboplatin & Paclitaxel

Regimen #1

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

Chemotherapy

21-day cycles

Regimen #2

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

Chemotherapy

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

21-day cycle for up to 10 cycles, until progression of disease, or unacceptable toxicity

Regimen #3

Study Evidence
Rao et al. 2006 Retrospective

Chemotherapy

28-day cycles

Regimen #4

Study Evidence
Rao et al. 2006 Retrospective

Chemotherapy

21-day cycles

References

  1. 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 contains verified protocol PubMed
  2. 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
  3. 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
  4. 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

Carboplatin & Paclitaxel, nanoparticle albumin-bound

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Regimen

Study Evidence
Kottschade et al. 2011 (N057E(1)) Phase II

Chemotherapy

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

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."

References

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

Carboplatin, Paclitaxel, Sorafenib

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CPS: Carboplatin, Paclitaxel, Sorafenib

Regimen

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

Chemotherapy

  • Carboplatin (Paraplatin) as follows:
    • Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
    • Cycles 5 to 10: 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
    • Cycles 5 to 10: 175 mg/m2 IV over 3 hours once on day 1, given first
  • Sorafenib (Nexavar) 400 mg PO BID on days 2 to 19

21-day cycle for 10 cycles, followed by:

Sorafenib monotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. 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
  2. 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

Cisplatin, Dacarbazine +/- Carmustine

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Regimen

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

Chemotherapy

21-day cycle for 6 cycles

References

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

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

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Regimen

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

Chemotherapy

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

21-day cycle for 6 cycles

References

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

Cisplatin, Paclitaxel, Dacarbazine

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Regimen

Study Evidence
Papadopoulos et al. 2009 Phase II

Chemotherapy

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

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CVD: Cisplatin, Vinblastine, Dacarbazine

Regimen #1

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

Chemotherapy

21-day cycle for up to 4 cycles

Supportive medications

Regimen #2

Study Evidence Comparator Efficacy
Eton et al. 2002 Phase III Sequential biochemotherapy Inferior TTP

Chemotherapy

42-day cycle for up to 5 cycles

References

  1. 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
  2. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains verified protocol link to PMC article PubMed

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

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CVD: Cisplatin, Vinblastine, Dacarbazine

Example orders

Regimen #1

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

Chemotherapy

Supportive medications

21-day cycle for up to 4 cycles

Regimen #2

Study Evidence Comparator Efficacy
Eton et al. 2002 Phase III CVD Superior TTP

Chemotherapy

42-day cycle for up to 5 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 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. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains verified protocol link to PMC article PubMed

Dacarbazine monotherapy

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Example orders

Regimen #1

Study Evidence Comparator Efficacy
Chapman et al. 2011 (BRIM-3) Phase III Vemurafenib Inferior OS
Hauschild et al. 2012 (BREAK-3) Phase III Dabrafenib Inferior PFS
Flaherty et al. 2012 (METRIC) Phase III Trametinib Seems to have inferior OS
Robert et al. 2014 (CheckMate 066) Phase III Nivolumab Inferior OS
Weber et al. 2015 (CheckMate 037) Phase III Nivolumab Inferior ORR
Hersh et al. 2015 Phase III nab-Paclitaxel Seems to have inferior PFS
Dummer et al. 2017 (NEMO) Phase III Binimetinib Inferior PFS

Patients in BRIM-3 had a BRAF p.V600E mutation detected. Patients in NEMO had NRAS mutations.

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study Evidence Comparator Efficacy
Robert et al. 2011 (CA184-024) Phase III Dacarbazine & Ipilimumab Inferior OS

Chemotherapy

21-day cycle for 8 cycles

Regimen #3

Study Evidence Comparator Efficacy
Middleton et al. 2000 Phase III Temozolomide Seems to have inferior PFS

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

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. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. link to original article contains verified protocol link to PMC article PubMed
    1. Update: McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. Epub 2014 Feb 7. link to PMC article PubMed
  3. Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article PubMed
  4. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25. link to original article contains verified protocol PubMed
  5. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
  6. 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
  7. 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
  8. Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains verified protocol PubMed
  9. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozón V, Long GV, Flaherty K. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. Epub 2017 Mar 8. link to original article PubMed

Dacarbazine & Ipilimumab

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Regimen

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

Chemotherapy

21-day cycle for 8 cycles

If patient has stable disease or objective response, proceed to maintenance ipilimumab.

References

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

Docetaxel monotherapy

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Regimen

Study Evidence
Aamdal et al. 1994 Phase II

Chemotherapy

Supportive medications

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

21-day cycles

References

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

High-dose (HD) IL-2

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Example orders

Regimen

Study Evidence
Atkins et al. 1999 Phase II

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

6 to 12 weeks per cycle for up to 5 cycles

Supportive medications

References

  1. 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
  2. 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

Imatinib monotherapy

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Regimen #1

Study Evidence
Hodi et al. 2013 Phase II

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

Starting dose

Given until disease progression; then proceed to higher dose:

Higher dose

Given until disease progression

Regimen #2

Study Evidence
Carvajal et al. 2011 Phase II

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

Chemotherapy

Given until disease progression

References

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

Ipilimumab monotherapy

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Example orders

Regimen #1

Study Evidence Comparator Efficacy Toxicity
Hodi et al. 2010 (MDX010-20) Phase III Ipilimumab & gp100 peptide vaccine Seems not superior
gp100 peptide vaccine Superior OS
Robert et al. 2015 (KEYNOTE-006) Phase III Pembrolizumab 10 mg/kg q2wks Inferior OS
Pembrolizumab 10 mg/kg q3wks Inferior OS
Postow et al. 2015 (CheckMate 069) Phase III Ipilimumab & Nivolumab Inferior PFS
Larkin et al. 2015 (CheckMate 067) Phase III Ipilimumab & Nivolumab Inferior PFS Equivalent HRQoL
Nivolumab Inferior PFS Equivalent HRQoL

Immunotherapy

21-day cycle for 4 cycles

Regimen #2

Study Evidence
Wolchok et al. 2010 Phase II
O'Day et al. 2010 Phase II
Margolin et al. 2012 Phase II

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

Immunotherapy

21-day cycle for 4 cycles

Patients in O'Day et al. 2010 and Margolin et al. 2012 who were clinically stable could proceed to ipilimumab maintenance.

References

  1. 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
  2. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains verified protocol link to PMC article PubMed
    1. Update: McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. link to original article PubMed
  3. 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
  4. 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
  5. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19.link to original article contains verified protocol PubMed
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Aug 16. [Epub ahead of print] link to original article PubMed
  6. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
  7. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed

Ipilimumab & Nivolumab

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Regimen #1

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

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

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

14-day cycles

Regimen #2

Study Evidence Comparator Efficacy
Postow et al. 2015 (CheckMate 069) Phase III Ipilimumab Superior PFS

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

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

21-day cycle for 4 cycles

Treatment followed by 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
  2. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. link to original article PubMed
  3. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed

Ipilimumab, then Nivolumab

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Regimen

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

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

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

14-day cycle for 6 cycles

Treatment followed by maintenance nivolumab.

References

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

Nivolumab monotherapy

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Regimen #1

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

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, given until progression of disease or unacceptable toxicity

Regimen #2

Study Evidence
Weber et al. 2013 Phase I

Immunotherapy

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

14-day cycle for 12 cycles

Treatment followed by maintenance nivolumab.

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. 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
  3. 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
  4. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article PubMed

Nivolumab, then Ipilimumab

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Regimen

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

Immunotherapy, part 1

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

14-day cycle for 6 cycles, followed by:

Immunotherapy, part 2

21-day cycle for 4 cycles

Treatment followed by maintenance nivolumab.

References

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

Paclitaxel monotherapy

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Example orders

Regimen #1

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

This was a therapy option for patients in the control arm of METRIC.

Chemotherapy

21-day cycles

Regimen #2

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

This was the control arm of SYMMETRY, which was a negative study.

Chemotherapy

28-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
  2. 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

Paclitaxel, nanoparticle albumin-bound monotherapy

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Regimen #1

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

Chemotherapy

28-day cycles

Regimen #2

Study Evidence
Hersh et al. 2012 Phase II

Note: this dose was intended for previously treated patients.

Chemotherapy

28-day cycles

References

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

Pembrolizumab monotherapy

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Regimen #1, 10 mg/kg q2wk

Study Evidence Comparator Efficacy
Robert et al. 2015 (KEYNOTE-006) Phase III Ipilimumab Superior OS
Pembrolizumab 10 mg/kg q3wk Seems not superior

Immunotherapy

14-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2, 10 mg/kg q3wk

Study Evidence Comparator Efficacy
Ribas et al. 2015 (KEYNOTE-002) Randomized Phase II Investigator-choice chemotherapy Superior PFS
Pembrolizumab 2 mg/kg Seems not superior
Robert et al. 2015 (KEYNOTE-006) Phase III Ipilimumab Superior OS
Pembrolizumab 10 mg/kg q2wk Seems not superior

Immunotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #3, 2 mg/kg q3wk

Study Evidence Comparator Efficacy
Ribas et al. 2015 (KEYNOTE-002) Randomized Phase II Investigator-choice chemotherapy Superior PFS
Pembrolizumab 10 mg/kg q3wk Seems not superior

Robert et al. 2014 and Ribas et al. 2015 investigated the 2 mg/kg and 10 mg/kg doses. 2 mg/kg is the FDA approved dose.

Immunotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

References

  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
  2. Phase I: 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 Jul 14. link to original article contains verified protocol PubMed
  3. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. link to original article contains verified protocol PubMed
  4. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19.link to original article contains verified protocol PubMed
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Aug 16. [Epub ahead of print] link to original article PubMed

Temozolomide monotherapy

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Regimen

Study Evidence Comparator Efficacy
Middleton et al. 2000 Phase III Dacarbazine Seems to have superior PFS

Chemotherapy

28-day cycles, given until progression of disease or unacceptable toxicity

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

Temozolomide & Bevacizumab

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TB: Temozolomide & Bevacizumab

Regimen

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

Chemotherapy

28-day cycles, given until progression of disease

References

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

Maintenance immunotherapy for metastatic or unresectable disease

IL-2 monotherapy

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Example orders

Regimen

Study Evidence
O'Day et al. 2002 Phase II

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

Supportive medications

28-day cycles, alternating with pulse cycles:

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

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

Supportive medications

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

References

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

Ipilimumab monotherapy

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Regimen

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

Preceding treatment

Immunotherapy

12-week cycles, given until progression of disease or unacceptable toxicity

References

  1. O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains verified protocol PubMed
  2. Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, 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
  3. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains protocol PubMed

Ipilimumab & Nivolumab

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Regimen

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

Preceding treatment

Immunotherapy

12-week cycle for 8 cycles

References

  1. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article PubMed

Nivolumab monotherapy

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Regimen #1, indefinite

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

Preceding treatment

Immunotherapy

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

14-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2, 2-year course

Study Evidence
Weber et al. 2013 Phase I

Preceding treatment

Immunotherapy

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

12-week cycle for 2 years

References

  1. Phase I: Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. contains verified protocol link to PMC article PubMed
  2. 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