Malignant Melanoma Treatment Protocols

Medically Reviewed by Gabriela Pichardo, MD on March 05, 2022

Treatment by Stage

Stage 0 in situ and IA{ref1}:

  • For patients with stage I and stage IA (≤1 mm thick, no ulceration, mitotic rate < 1/mm2 with no adverse features) melanoma, treatment recommendations include wide-excision surgery
  • For patients with stage IA (≤1 mm thick, no ulceration, mitotic rate < 1/mm2 with one or more adverse features), consider wide-excision surgery and discussion of sentinel lymph node biopsy (SLNB)

Stage IB and IIA{ref1}:

  • Discuss and offer patients SLNB and wide-excision surgery

Stage IIB or IIC{ref1}:

  • Surgery is recommended for stage IIB or IIC; also discuss or offer SLNB
  • If SLNB is performed and node positive, then complete dissection of nodal basin should be performed
  • Alternatively, observation can be recommended or clinical trial or interferon alfa
  • Use of interferon alfa is based on lower level of clinical evidence, and its use should be individualized

Stage III{ref1}:

  • For stage III (clinically positive nodes), surgical excision is recommended with complete lymph node dissection; adjuvant therapy may include observation, interferon alfa, nivolumab, or ipilimumab.
  • Consider radiation therapy to nodal basin if stage IIIC disease is present with multiple nodes involved or macroscopic extranodal extension
  • If stage III (sentinel node positive), primary treatment is clinical trial or lymph node dissection; adjuvant treatment includes clinical trial or observation or interferon alfa-2b (20 million IU/m2 IV five times weekly for 4 wk, then 10 million IU/m2 SC 3 times weekly for 48wk; treat for a total of 1 y)
  • Peginterferon alfa-2b (Pegintron) has been approved for adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 d of definitive surgical resection including complete lymphadenectomy; dosing recommendations are 6 μg/kg/wk SC for eight doses followed by 3 μg/kg/wk SC for up to 5 y
  • Ipilimumab (Yervoy) is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy; the recommended regimen is 10 mg/kg IV q3wk for four doses followed by 10 mg/kg q12wk for up to 3 years{ref2}
  • Nivolumab (Opdivo) is an adjuvant therapy for patients who have undergone complete resection of melanoma with lymph node involvement or metastatic disease. Recommended dosage is 240 mg IV every two weeks until disease recurrence or unacceptable toxicity for up to one year.

  • Nivolumab-relatlimab-rmbw (Opdualag) is a fixed-dose combination of nivolumab and relatlimab, administered as a single intravenous infusion for patients aged 12 years or older with unresectable or metastatic melanoma.

For patients with stage III in-transit disease, primary treatment options include the following:

  • Complete resection (preferred, if feasible)
  • SLNB for resectable disease
  • Hyperthermic perfusion/infusion with melphalan for localized multiple lesions in a single extremity or recurrent lesions in a single limb
  • Clinical trial
  • Intralesional injection (bacillus Calmette-Guérin [BCG], interferon alfa)
  • Local ablation therapy
  • Systemic therapy
  • Topical imiquimod (Aldara, Zyclara)

Stage IV with distant metastasis{ref1}:

  • Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)
  • If limited disease, resection is recommended; alternatively, observation or systemic therapy
  • Treatment for limited disease includes clinical trial or systemic therapy with interleukin-2 (IL-2) or temozolomide (Temcad, Temodar, Temodal), dacarbazine, or paclitaxel (Onxal, Taxol) based chemotherapy for two to three cycles, ipilumimab q3 wk four times, and then assessment for response; if stable, continue treatment (see below for drug regimens)
  • For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous disease
  • For stage IV disease in one limb, recommendations include surgery plus lymph perfusion treatment plus options such as observation, clinical trial, or treatment with interferon alfa

Single-Agent Treatment for Advanced or Metastatic Melanoma

Stage IV{ref3}{ref4}{ref5}{ref6}{ref7}{ref8}{ref9}:

  • Clinical trial is preferred
  • Pembrolizumab (Keytruda) 2 mg/kg IV q21d until disease progression or unacceptable toxicity; it is indicated as first-line treatment for unresectable or metastatic malignant melanoma; note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk{ref20} or
  • Ipilimumab (Yervoy) 3 mg/kg IV over 90 min; q21 d for a total of four doses{ref10}or
  • Dacarbazine 2-4.5 mg/kg/day IV for 10 days; may repeat q4 wk; or 250 mg/m2 IV on days 1-5; may repeat q3 wk or
  • Temozolomide  (Temodar) 150 mg/m2 PO on days 1-5; repeat q28 days; may increase dose to 200 mg/m2 PO on days 1-5 or
  • Interleukin-2 600,000 U/kg IV q8h (maximum 14 doses); following nine days of rest, repeat for another 14 doses (maximum 28 doses per course, as tolerated; FDA-approved recommendation) or
  • Nivolumab (Opdivo) 3 mg/kg IV q2wk until disease progression or unacceptable toxicity; single agent in the first-line treatment of unresectable or metastatic BRAF V600 wild-type or mutation-positive melanoma{ref21}

See the list below:

  • Dabrafenib (Tafinlar) 150 mg PO BID (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma
  • Trametinib (Mekinist) 2 mg PO qd (for BRAF V600E or V600K mutations); not indicated in patients who have received prior BRAF inhibitor therapy
  • Vemurafenib (Zelboraf) 960 mg PO q12 h (for patients with BRAF V600E mutation); not indicated for wild-type BRAF melanoma

Combination-Treatment Recommendations for Advanced or Metastatic Disease

Stage IV{ref3}{ref4}{ref5}{ref11}{ref12}{ref13}{ref14}:

  • Nivolumab 1 mg/kg IV over 60 min followed by ipilimumab 3 mg/kg IV over 90 min administered on the same day q3wk for 4 doses for BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma in previously untreated patients; subsequent single-agent nivolumab doses are 3 mg/kg IV q2wk until disease progression or unacceptable toxicity{ref13}{ref21}or
  • Dacarbazine 220 mg/m2 IV on days 1-3 plus carmustine 150 mg/m2 IV on day 1 plus cisplatin 25 mg/m2 IV on days 1-3; repeat cycle with dacarbazine and cisplatin q21 days; repeat cycle of carmustine q42 days or
  • Interferon alfa-2b (15 million IU/m2 IV on days 1-5, 8-12, and 15-19 as induction therapy or 10 million IU/m2 SC 3 times weekly after induction therapy) plus dacarbazine 200 mg/m2 IV on days 22-26 or

For patients with BRAF mutations, regimens are as follows:

  • Trametinib 2 mg PO qd plus dabrafenib 150 mg PO BID for unresectable or metastatic melanoma with BRAF V600E or V600K mutations{ref15}
  • Cobimetinib (Cotellic) 60 mg PO qd on days 1-21 plus vemurafenib 960 mg PO BID on days 1-28 of an every 28-day cycle for unresectable or metastatic melanoma in patients with BRAF V600E or V600K mutations{ref14}

Treatment for Disease Progression Following Ipilimumab and BRAF Inhibitor Treatment

Treatment options for unresectable or metastatic melanoma and disease progression following ipilimumab treatment are as follows:

  • Pembrolizumab 2 mg/kg IV q21 days until disease progression or unacceptable toxicity and, if BRAF V600 mutation positive, a BRAF inhibitor{ref12}
  • Nivolumab 3 mg/kg IV q14 days until disease progression or unacceptable toxicity; and, if BRAF V600 mutation positive, a BRAF inhibitor{ref16}

Oncolytic Immunotherapy

Talimogene laherparepvec (Imlygic) is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery{ref17}

It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance

Dosage and volume of the injection(s) depend on whether it is the initial dose, second dose, or subsequent doses and by lesion size

Return to the Metastatic Melanoma Guide

Show Sources

1. NCCN Clinical Practice Guidelines in Oncology: Melanoma. V.3.2011. Available at Accessed: March 28, 2011.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. 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. [Medline].

3. Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, et al. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10. 23(35):9001-7. [Medline].

4. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA. 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. [Medline].

5. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S. 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. [Medline].

6. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. [Medline].

7. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28. 380(9839):358-65. [Medline].

8. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12. 367(2):107-14. [Medline].

9. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22. 372 (4):320-30. [Medline]. [Full Text].

10. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19. 363(8):711-23. [Medline].

11. 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. [Medline].

12. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. 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. [Medline].

13. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21. 372 (21):2006-17. [Medline].

14. Larkin J, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. Abstract 9006. Presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. May 29 – June 2, 2015. Chicago, IL. Available at Accessed: December 4, 2015.

15. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov. 367(18):1694-703. [Medline]. [Full Text].

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