Melanoma

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39 regimens on this page 75 variants on this page

Adjuvant therapy

Interferon alfa-2a (Roferon-A)

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Regimen #1

Study	Evidence	Comparator
[/fulltext Grob et al. 1998]	Phase III	Observation

Immunotherapy

• Interferon alfa-2a (Roferon-A) 3,000,000 international units SC three times per week

18-month course

Regimen #2

Study	Evidence	Comparator
Pehamberger et al. 1998	Phase III	Observation

Induction phase

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

21-day course, then proceed to maintenance phase

Maintenance phase

• Interferon alfa-2a (Roferon-A) 3,000,000 international units SC three times per week

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 (Intron-A)

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Example orders

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

Regimen #1

Study	Evidence	Comparator
Kirkwood et al. 1996 (ECOG EST 1684)	Phase III	Observation

Induction phase

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

4-week course, then proceed to maintenance phase

Maintenance phase

• Interferon alfa-2b (Intron-A) 10,000,000 units/m² SC three times per week

48-week course

Regimen #2

Study	Evidence	Comparator
Cameron et al. 2001 (The Scottish study)	Phase III	Observation

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

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

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 PubMed

Ipilimumab (Yervoy)

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Example orders

• Example orders for Ipilimumab (Yervoy) in melanoma

Regimen

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

Induction phase

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

21-day cycle for 4 doses

Maintenance phase

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

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

Peginterferon alfa-2b (Sylatron)

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Regimen

Study	Evidence	Comparator
Eggermont et al. 2008 (EORTC 18991)	Phase III	Observation

Patients enrolled in EORTC 18991 had resected stage III melanoma.

Induction phase

• Peginterferon alfa-2b (Sylatron) 6 mcg/kg SC once per week

8-week course, then proceed to maintenance phase

Maintenance phase

• Peginterferon alfa-2b (Sylatron) 3 mcg/kg SC once per week

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
Kirkwood et al. 1996 (ECOG EST 1684)	Phase III	Interferon alfa-2b
Pehamberger et al. 1998	Phase III	Interferon alfa-2a
Grob et al. 1998	Phase III	Interferon alfa-2a
Cameron et al. 2001 (The Scottish study)	Phase III	Interferon alfa-2b
Eggermont et al. 2008 (EORTC 18991)	Phase III	Pegylated interferon alfa-2b
Eggermont et al. 2015 (EORTC 18071)	Phase III	Ipilimumab

No active antineoplastic treatment. 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 PMC article contains verified protocol PubMed
5. 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
6. 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

Local therapy

Talimogene laherparepvec (Imlygic)

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Regimen

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

In Andtbacka et al. 2015, Talimogene laherparepvec (Imlygic) was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions.

• Talimogene laherparepvec (Imlygic) 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 < 0.5 cm to 4.0 mL for lesions > 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
Kottschade et al. 2013 (N0775)	Randomized Phase II	Temozolomide & Bevacizumab

The doses listed here are the amended starting doses.

Chemotherapy

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

28-day cycles, 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 PubMed

CP - Carboplatin & Paclitaxel

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CP: Carboplatin, Paclitaxel

Regimen #1

Study	Evidence	Comparator
Hauschild et al. 2009	Phase III	Carboplatin, Paclitaxel, Sorafenib
Flaherty et al. 2013 (E2603)	Phase III	Carboplatin, Paclitaxel, Sorafenib

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 #2

Study	Evidence
Rao et al. 2006	Retrospective

Chemotherapy

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

28-day cycles

Regimen #3

Study	Evidence
Rao et al. 2006	Retrospective

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 175 to 200 mg/m² IV once on day 1

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 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 PubMed

Carboplatin & Paclitaxel, nanoparticle albumin-bound

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Regimen

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

Chemotherapy

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

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 PubMed

Carboplatin, Paclitaxel, Sorafenib

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Regimen

Study	Evidence	Comparator
Hauschild et al. 2009	Phase III	Carboplatin & Paclitaxel
Flaherty et al. 2013 (E2603)	Phase III	Carboplatin & Paclitaxel

Hauschild et al. 2009 and Flaherty et al. 2013 (E2603) were negative studies. They did not show improved outcomes for Carboplatin, Paclitaxel, Sorafenib as compared to Carboplatin and Paclitaxel.

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 225 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 4 cycles, then

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 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 6 cycles, until progression of disease, or unacceptable toxicity; then proceed to sorafenib monotherapy

Sorafenib monotherapy

• Sorafenib (Nexavar) 400 mg PO BID on days 1 to 21

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 PubMed

Cisplatin, Dacarbazine +/- Carmustine

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Regimen

Study	Evidence	Comparator
Ridolfi et al. 2002	Phase III	Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine

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

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
Ridolfi et al. 2002	Phase III	Cisplatin, Dacarbazine +/- Carmustine

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

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4
• Paclitaxel (Taxol) 100-120 mg/m² IV once per day on days 1 & 8
• Dacarbazine (DTIC) 800 mg/m² IV once on day 1

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
Atkins et al. 2008 (ECOG E3695)	Phase III	Sequential biochemotherapy

Chemotherapy

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

21-day cycle for up to 4 cycles

Supportive medications

• Antiemetics and Dexamethasone (Decadron) premedication for chemotherapy

Regimen #2

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

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4, 22 to 25
• Vinblastine (Velban) 2 mg/m² IV once per day on days 1 to 4, 22 to 25
• Dacarbazine (DTIC) 800 mg/m² IV once per day on days 1 & 22

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 PubMed

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

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CVD: Cisplatin, Vinblastine, Dacarbazine

Example orders

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

Regimen #1

Study	Evidence	Comparator
McDermott et al. 2000	Phase II
Atkins et al. 2008 (ECOG E3695)	Phase III	CVD

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 to 4, given first
• Vinblastine (Velban) 1.2 mg/m² IV push once per day on days 1 to 4, given second
• Dacarbazine (DTIC) 800 mg/m² IV over 1 hour once on day 1, given third
• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m²/day IV continuous infusion over 96 hours on days 1 to 4
• Interferon alfa-2b (Intron-A) 5,000,000 units/m² SC once per day on days 1 to 5, 8, 10, 12; doses on days 8, 10, 12 are given as outpatient doses

21-day cycle for up to 4 cycles

Supportive medications

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

Regimen #2

Study	Evidence	Comparator
Eton et al. 2002	Phase III	CVD

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 4, 22 to 25
• Vinblastine (Velban) 1.5 mg/m² IV once per day on days 1 to 4, 22 to 25
• Dacarbazine (DTIC) 800 mg/m² IV once per day on days 1 & 22
• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m²/day IV continuous infusion over 96 hours on days 5 to 8, 17 to 20, 26 to 29
• Interferon alfa-2b (Intron-A) 5,000,000 units/m² SC once per day on days 5 to 9, 17 to 21, 26 to 30

6-week cycle for up to 5 cycles

References

1. 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
2. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains verified protocol PubMed
3. 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 PubMed

Dabrafenib (Tafinlar)

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Regimen

Study	Evidence	Comparator
Hauschild et al. 2012	Phase III	Dacarbazine
Flaherty et al. 2012	Phase III	Dabrafenib & Trametinib
Long et al. 2012 (BREAK-MB)	Phase II

Patients enrolled in these trials were BRAF-mutated.

Chemotherapy

• Dabrafenib (Tafinlar) 150 mg PO BID

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 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

Dabrafenib & Trametinib

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Regimen

Study	Evidence	Comparator
Flaherty et al. 2012	Phase III	Dabrafenib

Patients enrolled in Flaherty et al. 2012 were BRAF-mutated.

Chemotherapy

• Dabrafenib (Tafinlar) 150 mg PO BID
• Trametinib (Mekinist) 2 mg PO once per day

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 PubMed

Dacarbazine (DTIC)

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Example orders

• Example orders for Dacarbazine (DTIC) in melanoma

Regimen #1

Study	Evidence	Comparator
Chapman et al. 2011 (BRIM-3)	Phase III	Vemurafenib
Hauschild et al. 2012	Phase III	Dabrafenib
Flaherty et al. 2012 (METRIC)	Phase III	Trametinib
Robert et al. 2014	Phase III	Nivolumab
Weber et al. 2015 (CheckMate 037)	Phase III	Nivolumab

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

Chemotherapy

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

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

Regimen #2

Study	Evidence	Comparator
Robert et al. 2011	Phase III	Dacarbazine & Ipilimumab

Chemotherapy

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

21-day cycle for 8 cycles

Regimen #3

Study	Evidence	Comparator
Middleton et al. 2000	Phase III	Temozolomide

Chemotherapy

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

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. 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 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
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

Dacarbazine & Ipilimumab

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Regimen

Study	Evidence	Comparator
Robert et al. 2011	Phase III	Dacarbazine

Chemotherapy

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

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

Docetaxel (Taxotere)

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Regimen

Study	Evidence
Aamdal et al. 1994	Phase II

Chemotherapy

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

Supportive medications

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

21-day cycles

References

1. Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J. 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

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

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

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

References

1. 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

• Example orders for IL-2 maintenance biotherapy in melanoma

Regimen

Study	Evidence
O'Day et al. 2002	Phase II

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

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

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

Supportive medications

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

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: IL-2 - Aldesleukin (Proleukin) 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

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

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 (Gleevec)

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Regimen

Study	Evidence
[Hodi et al. 2013]	Phase II

Patients in Hodi et al. 2013 had melanomas arising from mucosal, acral, and chronically sun-damaged (CSD) skin with KIT mutations or amplifications.

Starting dose

• Imatinib (Gleevec) 400 mg PO once per day

‘’’Given until disease progression; then proceed to higher dose

Higher dose

• Imatinib (Gleevec) 400 mg PO BID

‘’’Given until disease progression

References

1. 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 PubMed

Ipilimumab (Yervoy)

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Example orders

• Example orders for Ipilimumab (Yervoy) in melanoma

Regimen #1

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Hodi et al. 2010	Phase III	10.9% (95% CI 6.3 - 17.4)	Ipilimumab & gp100 peptide vaccine gp100 peptide vaccine	5.7% (95% CI 3.7 - 8.4) 1.5% (95% CI 0.2 - 5.2)	Pretreated (chemo, IL-2)
Robert et al. 2015 (KEYNOTE-006)	Phase III		Pembrolizumab
Postow et al. 2015	Phase III		Ipilimumab & Nivolumab

Immunotherapy

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

21-day cycle for 4 cycles

Regimen #2

Study	Evidence
Wolchok et al. 2010	Phase II

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1
  • Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study

21-day cycle for 4 cycles

Regimen #3

Study	Evidence
O'Day et al. 2010	Phase II

Induction phase

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

21-day cycle for 4 cycles

Maintenance phase

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

12-week cycles, given until progression of disease or unacceptable toxicity; starts 12 weeks after completion of induction phase

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. link to original article contains verified protocol 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. 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
5. 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

Ipilimumab & Nivolumab

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Regimen

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Postow et al. 2015	Phase III	BRAFwt: 61% (95% CI 49 - 72) BRAF V600mut: 52% (95% CI 31 - 73)	Ipilimumab	BRAFwt: 11% (95% CI 3 - 25) BRAF V600mut: 10% (95% CI 0 - 45)	Treatment naive, no brain mets

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."

Induction therapy

• Ipilimumab (Yervoy) 3 mg/kg IV once on day 1, given second
• Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first

21-day cycle for 4 cycles, then proceed to Nivolumab only phase

Nivolumab only phase

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

21-day cycle for 4 cycles, then proceed to maintenance therapy

Maintenance therapy

• Ipilimumab (Yervoy) 3 mg/kg IV once on day 1, given second
• Nivolumab (Opdivo) 1 mg/kg IV once on day 1, given first

12-week cycle for 8 cycles

References

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

Nivolumab (Opdivo)

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Regimen #1

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Robert et al. 2014	Phase III	40.0% (95% CI 33.3 - 47.0)	Dacarbazine	13.9% (95% CI 9.5 - 19.4)	Treatment naive for metastatic disease
Weber et al. 2015 (CheckMate 037)	Phase III	31.7% (95% CI 23.5 - 40.8)	Dacarbazine or Carboplatin & Paclitaxel	10.6% (95% CI 3.5 - 23.1)	Ipilimumab exposed ± other treatments

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

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

Regimen #2, Weber et al. 2013

Level of Evidence: Phase I

Induction therapy

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

2-week cycle for 12 cycles, then proceed to maintenance therapy

Maintenance therapy

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

12-week cycle for 2 years

References

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

Paclitaxel (Taxol)

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Example orders

• Example orders for Paclitaxel (Taxol) in melanoma

Regimen #1

Study	Evidence	Comparator
Flaherty et al. 2012 (METRIC)	Phase III	Trametinib

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

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

Regimen #2

Study	Evidence	Comparator
O'Day et al. 2013 (SYMMETRY)	Phase III	Elesclomol & Paclitaxel

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

Chemotherapy

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

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

Pembrolizumab (Keytruda)

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Regimen #1, 10 mg/kg q2wk

Study	Evidence	Comparator
Ribas et al. 2015 (KEYNOTE-002)	Randomized Phase II	Investigator-choice chemotherapy Pembrolizumab 10 mg/kg
Robert et al. 2015 (KEYNOTE-006)	Phase III	Ipilimumab Pembrolizumab 10 mg/kg q3wk

Immunotherapy

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

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

Regimen #2, 10 mg/kg q3wk

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Ribas et al. 2015 (KEYNOTE-002)	Randomized Phase II		Investigator-choice chemotherapy Pembrolizumab 2 mg/kg
Robert et al. 2015 (KEYNOTE-006)	Phase III	32.9% (95% CI 27.4 - 38.7)	Ipilimumab Pembrolizumab 10 mg/kg q2wk	11.9% (95% CI 8.3 - 16.3) 33.7% (95% CI 28.2 - 39.6)	Mixed; 2:1 (treatment naive : exposed)

Immunotherapy

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

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

Regimen #3, 2 mg/kg q3wk

Study	Evidence	ORR	Comparator	Comparator ORR	Pt Population
Ribas et al. 2015 (KEYNOTE-002)	Randomized Phase II	21% (95% CI 15 - 28)	Investigator-choice chemotherapy Pembrolizumab 10 mg/kg q3wk	4% (95% CI 2 - 9) 25% (95% CI 19 - 32)	Ipi exposed ± other therapies

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

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

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

References

1. 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
2. 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
3. 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 (Temodar)

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Regimen

Study	Evidence	Comparator
Middleton et al. 2000	Phase III	Dacarbazine

Chemotherapy

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

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. link to original article contains verified protocol PubMed

Temozolomide & Bevacizumab (TB)

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Regimen

Study	Evidence	Comparator
Kottschade et al. 2013 (N0775)	Randomized Phase II	ABC

Chemotherapy

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

28-day cycles, 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 PubMed

Trametinib (Mekinist)

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Regimen

Study	Evidence	Comparator
Flaherty et al. 2012 (METRIC)	Phase III	Dacarbazine Paclitaxel
Kim et al. 2012	Phase II

Chemotherapy

• Trametinib (Mekinist) 2 mg PO once per day

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 original article contains verified protocol 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 PubMed

Vemurafenib (Zelboraf)

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Regimen

Study	Evidence	Comparator
Chapman et al. 2011 (BRIM-3)	Phase III	Dacarbazine
Larkin et al. 2014 (coBRIM)	Phase III	Vemurafenib & Cobimetinib

Patients enrolled in BRIM-3 had a BRAF p.V600E mutation detected.

Chemotherapy

• Vemurafenib (Zelboraf) 960 mg PO BID

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 PubMed
2. 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

Vemurafenib & Cobimetinib

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Regimen

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

Patients enrolled in coBRIM had a BRAF V600 mutation.

Chemotherapy

• Vemurafenib (Zelboraf) 960 mg PO BID on days 1 to 28
• Cobimetinib (Cotellic) 60 mg PO once per day on days 1 to 21

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

Consolidation and/or maintenance after upfront therapy

Ipilimumab (Yervoy)

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Regimen

Study	Evidence
Robert et al. 2011	Non-randomized

Treatment preceded by dacarbazine & ipilimumab.

Immunotherapy

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

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

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