Melanoma

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38 regimens on this page
56 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

Induction phase

21-day course, then proceed to maintenance phase

Maintenance phase

49-week course (to complete a total 1-year treatment when added to the induction phase)

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

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

Induction phase

4-week course, then proceed to maintenance phase

Maintenance phase

48-week course

Regimen #2

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

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Example orders

Regimen

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

Treatment preceded by complete resection of stage III cutaneous melanoma.

Induction phase

21-day cycle for 4 doses, followed by:

Maintenance phase

3-month cycle for up to 3 years or 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 AM1, Chiarion-Sileni V1, Grob JJ1, Dummer R1, Wolchok JD1, Schmidt H1, Hamid O1, Robert C1, Ascierto PA1, Richards JM1, Lebbé C1, Ferraresi V1, Smylie M1, Weber JS1, Maio M1, Bastholt L1, Mortier L1, Thomas L1, Tahir S1, Hauschild A1, Hassel JC1, Hodi FS1, Taitt C1, de Pril V1, de Schaetzen G1, Suciu S1, Testori A1. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov;375(19):1845-55. Epub 2016 Oct 7. 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.

Induction phase

8-week course, then proceed to maintenance phase

Maintenance phase

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
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
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.

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 AM1, Chiarion-Sileni V1, Grob JJ1, Dummer R1, Wolchok JD1, Schmidt H1, Hamid O1, Robert C1, Ascierto PA1, Richards JM1, Lebbé C1, Ferraresi V1, Smylie M1, Weber JS1, Maio M1, Bastholt L1, Mortier L1, Thomas L1, Tahir S1, Hauschild A1, Hassel JC1, Hodi FS1, Taitt C1, de Pril V1, de Schaetzen G1, Suciu S1, Testori A1. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov;375(19):1845-55. Epub 2016 Oct 7. link to original article contains verified protocol 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.

  • 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

CP - 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 - Cisplatin, Vinblastine, Dacarbazine

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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

6-week 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

6-week 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

Dabrafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Hauschild et al. 2012 (BREAK-3) Phase III Dacarbazine Superior PFS
Flaherty et al. 2012 Randomized Phase II Dabrafenib & Trametinib Inferior PFS
Long et al. 2012 (BREAK-MB) Phase II
Long et al. 2014 Randomized Phase II Dabrafenib & Trametinib Seems to have inferior OS

Patients enrolled in these trials were BRAF-mutated.

Chemotherapy

Given until progression of disease

References

  1. 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
  2. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. Epub 2012 Sep 29. link to original article contains verified protocol link to PMC article PubMed
  3. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. Epub 2012 Oct 8. link to original article contains verified protocol PubMed
  4. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. Epub 2014 Sep 29. link to original article PubMed
    1. Update: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. Epub 2015 May 31. link to original article PubMed

Dabrafenib & Trametinib

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Regimen

Study Evidence Comparator Efficacy
Flaherty et al. 2012 Randomized Phase II Dabrafenib Superior PFS
Long et al. 2014 Phase III Dabrafenib Seems to have superior OS

Chemotherapy

Continued until progression

References

  1. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. Epub 2012 Sep 29. link to original article contains verified protocol link to PMC article PubMed
  2. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. Epub 2014 Sep 29. link to original article PubMed
    1. Update: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. Epub 2015 May 31. link to original 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 Mar 8. [Epub ahead of print] 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

IL-2 maintenance biotherapy

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Example orders

Regimen

Study Evidence
O'Day et al. 2002 Phase II

Low-dose cycles 1, 4, 7, 9, 11

28-day cycle for a total of 12 cycles after being combined with the pulse cycles below

Supportive medications

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

28-day cycle for a total of 12 cycles after being combined with the low dose cycles above

Supportive medications

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

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
Hodi et al. 2010 (MDX010-20) Phase III Ipilimumab & gp100 peptide vaccine
gp100 peptide vaccine Superior OS
Robert et al. 2015 (KEYNOTE-006) Phase III Pembrolizumab 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
Nivolumab Inferior PFS

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
  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

Ipilimumab & Nivolumab

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Regimen #1

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

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

Ipilimumab -> Nivolumab

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Regimen

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

Immunotherapy, part 1

3-week 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.

2-week 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 Pt Population
Robert et al. 2014 (CheckMate 066) Phase III Dacarbazine Superior OS Treatment naive for metastatic disease
Weber et al. 2015 (CheckMate 037) Phase III Dacarbazine
Carboplatin & Paclitaxel
Superior ORR Ipilimumab exposed ± other treatments
Larkin et al. 2015 (CheckMate 067) Phase III Ipilimumab Superior PFS
Ipilimumab & Nivolumab Inferior PFS

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.

2-week 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.

2-week 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

Nivolumab -> Ipilimumab

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Regimen

Study Evidence Comparator Efficacy
Weber et al. 2016 (CheckMate 064) Randomized Phase II Ipilimumab -> 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.

2-week cycle for 6 cycles, followed by:

Immunotherapy, part 2

3-week 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
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

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

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 (TB)

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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

Trametinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Flaherty et al. 2012 (METRIC) Phase III Dacarbazine
Paclitaxel
Seems to have superior OS
Kim et al. 2012 Phase II

Chemotherapy

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. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT, Peddareddigari VG, Lebowitz PF, Le NT, Burris HA 3rd, Messersmith WA, O'Dwyer PJ, Kim KB, Flaherty K, Bendell JC, Gonzalez R, Kurzrock R, Fecher LA. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):782-9. Epub 2012 Jul 16. link to SD article contains verified protocol link to PMC article PubMed
  3. Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013 Feb 1;31(4):482-9. Epub 2012 Dec 17. link to original article contains verified protocol link to PMC article PubMed

Vemurafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Chapman et al. 2011 (BRIM-3) Phase III Dacarbazine Superior OS
Sosman et al. 2012 Phase II
Larkin et al. 2014 (coBRIM) Phase III Vemurafenib & Cobimetinib Inferior OS

Patients enrolled in BRIM-3 had a BRAF p.V600E or p.V600K mutation detected. Efficacy reported for coBRIM is based on the interim update.

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. 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
  2. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012 Feb 23;366(8):707-14. link to original article link to PMC article PubMed
  3. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. link to original article contains verified protocol PubMed
    1. Update: Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248-60. Epub 2016 Jul 30. link to original article PubMed

Vemurafenib & Cobimetinib

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Regimen

Study Evidence Comparator Efficacy
Larkin et al. 2014 (coBRIM) Phase III Vemurafenib Superior OS

Patients enrolled in coBRIM had a BRAF V600 mutation. Efficacy reported for coBRIM is based on the interim update.

Chemotherapy

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

References

  1. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. link to original article contains verified protocol PubMed
    1. Update: Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248-60. Epub 2016 Jul 30. link to original article PubMed

Consolidation and/or maintenance after upfront therapy

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

Treatment in O'Day et al. 2010 and Margolin et al. 2012 preceded by ipilimumab induction. Treatment in CA184-024 preceded by dacarbazine & ipilimumab.

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

Treatment preceded by ipilimumab & nivolumab induction.

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

Treatment preceded by nivolumab -> ipilimumab induction versus ipilimumab -> 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.

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

Regimen #2, 2-year course

Study Evidence
Weber et al. 2013 Phase I

Treatment preceded by 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 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