Attempts to develop combination regimens that incorporate chemotherapy, for example, multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9,10,11] and combinations of chemotherapy and immunotherapy [7,12,13,14,15,16,17] have not demonstrated an improvement of the combination on OS.
In smaller subsets of melanoma, activating mutations may occur in NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.
Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.
Ipilimumab is a human monoclonal antibody that blocks the activity of CTLA-4, blocking the function of CTLA-4 as a down regulator of T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and supported by two prospective, randomized, international trials, one each in previously untreated and treated patients.[6,19]
Previously treated patients. A total of 676 patients with previously treated, unresectable stage III or stage IV disease, who were HLA-A*0201-positive patients, were entered into a three-arm, multinational, randomized, double-blind trial comparing ipilimumab with or without glycoprotein 100 (gp100) peptide vaccine to the gp100 vaccine plus placebo. Patients were stratified by baseline metastases and prior receipt or nonreceipt of IL-2 therapy. Of the patients, 82 had metastases to the brain at baseline. The median OS was 10 months and 10.1 months among patients receiving ipilimumab alone or with the gp100 vaccine, respectively, versus 6.4 months for patients receiving the vaccine alone (hazard ratio [HR], 0.68; P < .001; HR, 0.66; P < .003).
An analysis at 1 year showed that among those patients treated with ipilimumab, 44% and 45% of them were alive compared with 25% of the patients who received vaccine only. Grade 3 to grade 4 immune-related adverse events (AEs) occurred in 10% to 15% of patients treated with ipilimumab. These immune-related AEs most often included diarrhea or colitis, and endocrine-related events (i.e., inflammation of the pituitary) that required cessation of therapy and institution of anti-inflammatory agents, such as corticosteroids or in four cases, infliximab (i.e., an anti-tumor necrosis factor-alpha antibody). There were 14 deaths related to study drugs (2.1%), and seven were associated with immune-related AEs.[Level of evidence: 1iA]