Melanoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]-Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma

Treatment options for unresectable stage III, stage IV, and recurrent melanoma include the following:

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Melanoma, Malignant

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1. Immunotherapy.
   1. Checkpoint inhibitors.
      • Anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4): ipilimumab.
      • Anti-PD-1 (programmed cell death-1) and PD-L1 (programmed death ligand 1).
   2. High-dose interleukin-2 (IL-2).
   3. Dual immunomodulation.
2. Signal transduction inhibitors.
   1. BRAF (V-raf murinesarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
      • Vemurafenib.
      • Dabrafenib.
   2. MEK inhibitors.
      • Trametinib.
   3. Combination therapy with signal transduction inhibitors.
      • Dabrafenib plus trametinib.
      • Multikinase inhibitors.
   4. KIT inhibitors.
3. Chemotherapy.
4. Palliative local therapy.

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches-checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway-have demonstrated improvement in overall survival (OS) in randomized trials versus the use of dacarbazine (DTIC) or in comparison to DTIC. Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.

Immunotherapy

Checkpoint inhibitors

Anti-CTLA-4: ipilimumab

Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to down-regulate T-cell activation, proliferation, and effector function.

Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials, and was approved by the U.S. Food and Drug Administration (FDA) in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.[1,2]

Evidence (ipilimumab):

1. Previously treated patients: A total of 676 patients with previously treated, unresectable stage III or stage IV disease, and who were HLA-A*0201 positive, were entered into a three-arm, multinational, randomized (3:1:1), double-blind, double-dummy trial. A total of 403 patients were randomly assigned to receive ipilimumab (3 mg/kg every 3 weeks for 4 doses) with glycoprotein 100 (gp100) peptide vaccine. One hundred thirty-seven patients received ipilimumab (3 mg/kg every 3 weeks for 4 doses), and 136 patients received the gp100 vaccine. Patients were stratified by baseline metastases and previous receipt or nonreceipt of interleukin-2 (IL-2) therapy. Eighty-two of the patients had metastases to the brain at baseline.[2][Level of evidence: 1iA]
   • The median OS was 10 months among patients receiving ipilimumab alone and 10.1 months among those receiving ipilimumab with the gp100 vaccine, compared with 6.4 months for patients receiving the vaccine alone (hazard ratio [HR] of ipilimumab alone vs. gp100 alone, 0.66; P <.003; HR of ipilimumab plus vaccine vs. gp100 alone, 0.68; P < .001).
   • An analysis at 1 year showed that among patients treated with ipilimumab, 44% of those treated with ipilimumab and 45% of those treated with ipilimumab and the vaccine were alive, compared with 25% of the patients who received the vaccine only.
   • Grade 3 or grade 4 immune-related adverse events (irAEs) occurred in 10% to 15% of patients treated with ipilimumab. These irAEs most often included diarrhea or colitis, and endocrine-related events (e.g., inflammation of the pituitary). These events required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or, in four cases, infliximab (an antitumor necrosis factor-alpha antibody).
   • There were 14 drug-related deaths (2.1%), and seven deaths were associated with irAEs.
2. Previously untreated patients: A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to receive ipilimumab (10 mg/kg) plus DTIC (850 mg/m²) or placebo plus DTIC (850 mg/m²) at weeks 1, 4, 7, and 10 followed by DTIC alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of patients had stage M1c disease.[1][Level of evidence: 1iA]
   • The median OS was 11.2 months (95% confidence interval [CI], 9.4-13.6) for the ipilimumab-DTIC group, versus 9.1 months (95% CI, 7.8-10.5) for the placebo-DTIC group. Estimated survival rates in the ipilimumab-DTIC group were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years (HR for death, 0.72; P < .001); and in the placebo-DTIC group, the rates were 36.3% at 1 year, 17.9% at 2 years, and 12.2% at 3 years.
   • The most common study-drug-related adverse events (AEs) were those classified as immune related. Grade 3 or grade 4 irAEs were seen in 38.1% of patients treated with ipilimumab plus DTIC versus 4.4% of patients treated with placebo plus DTIC, the most common events were hepatitis and enterocolitis.
   • No drug-related deaths occurred.

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