Novel Therapies for the Treatment of Metastatic Melanoma

February 2012 | Volume 11 | Issue 2 | Features | 271 | Copyright © February 2012

Jason Chouake BS and Adam Friedman MD



Never has there been a more exciting period in the history of melanoma treatment. For many years, the only therapeutic option and most widely used single agent for the palliative therapy of metastatic melanoma was dacarbazine, with which only 1–2 percent of patients achieve a durable long-term response.1 This past year, the FDA has approved two new treatments for metastatic melanoma, vemurafenib and ipilimumab. Vemurafenib, the first selective BRAF inhibitor approved for clinical use, has demonstrated impressive single agent activity. Recent phase 3 trials showed an impressive risk reduction in the risk of early death from metastatic melanoma.2 Ipilimumab is a fully human monoclonal IgG1 κ antibody that binds to and inhibits cytotoxic T-lymphocyte antigen-4 (CTLA-4), and inhibits binding of CTLA-4 to B7 on antigen presenting cells (APCs). The approval of both of these therapies is a landmark in the treatment of metastatic melanoma, and soon even more efficacious therapies may be available for the treatment of this fatal disease. In addition to these new small molecule biologics, there are also emerging therapies for metastatic melanoma that target antitumor T-cells which are stimulated by immune modulators, such as IL-2 and ipilimumab. In fact, autologous T-cell transfer immunotherapy is one of the few emerging approaches to metastatic melanoma that mediates complete durable responses at clinically meaningful levels. These three novel therapeutic approaches will be reviewed herein.
BRAF is a component of the MAP kinase pathway. The MAP kinase pathway transmits growth stimulatory signals from the cell surface to the nucleus. BRAF is mutated in ∼50 percent of melanomas. The predominant mutation is a substitution of valine 600 to glutamate (V600E).3,4 The kinase activity of mutated BRAF is prodigious when compared to the wild type. Melanomas with mutated BRAF become dependent on the inherently stimulative growth signals, and in some settings, cell death can be induced when those signals are blocked. Vemurafenib is an orally available BRAF inhibitor that selectively targets the BRAF V600E isoform. It was approved by the FDA in August 2011 as a first line single agent therapy for the treatment of BRAF V600E positive malignant melanoma. Vemurafenib is an ATP-competitive inhibitor, highly preferential for mutant BRAF V600E. In a recently published phase 3 clinical trial comparing vemurafenib to dacarbazine, vemurafenib had superior progression-free survival (Table 1). Of 219 patients, 48 percent had a confirmed objective response, versus five percent for patients who received dacarbazine. The estimated median progression free survival was 5.3 months in the vemurafenib group.2,5
The most common adverse events were grade 1–2 arthralgia, rash, photosensitivity, fatigue, alopecia, pruritus, and skin papilloma, detected in about 25 percent of patients.6 One of the more unusual side effects of vemurafenib is the development of cutaneous squamous cell carcinomas in 20 percent of patients in phase 3 trials.2 These SCCs were completely resected with no further complications.
Despite initial response to vemurafenib treatment, acquired resistance eventually occurs, and patients relapse. Preclinical studies suggest that malignant cells reactivate oncogenic pathways following mutant BRAF inhibition.7 Additionally, 20 percent of patients with the V600E mutation are intrinsically resistant to vemurafenib.8
Ipilimumab is a fully human monoclonal antibody IgGκ that bind cytotoxic T-lymphocyte antigen-4 (CTLA-4), and prevents CTLA-4 from interacting with B7 on APCs. When expressed by regulatory T-cells, CTLA-4 stonewalls the activation of naïve T-cells, suppressing T-cell immunity. Ipilimumab improved overall survival in a phase 3 clinical study that looked at ipilimumab either alone, or with a gp100 vaccine in patients with metastatic melanoma who had undergone previous treatment. Median overall survival was 10.0 months in patients treated with ipilimumab as compared to 6.4 months in patients who received gp100 alone.9 In a second phase 3 clinical trial, ipilimumab plus dacarbazine for 502 patients with previously untreated melanoma was studied. Overall survival was 11.2 months in the ipilimumab and dacarbazine group versus 9.1 months in the dacarbazine plus placebo group, with higher survival rates at one, two, and three years. The best overall response for ipilimumab plus dacarbazine in patients with previously untreated metastatic melanoma was 15.2 percent, with complete response seen in 1.6 percent of patients.10 The adverse effects of ipilimumab are more consistent with those of other immunomodulatory agents. Immune-related adverse events (irAEs) are dose related, and the most common adverse effects are grade I and II irAEs of the skin (rash, pruritus) and autoimmune colitis (diarrhea).11 After 3–4 weeks, adverse effects of the skin are seen; after 6–7 weeks, side effects involving the GI tract are seen; and after an average of 9.2 weeks endocrine effects are apparent. The standard of care for treating irAEs is systemic corticosteroid administration. For any irAE grade II or higher, ipilimumab is held, and for any severe (grade III–IV) irAEs, prednisone 1–2 mg/kg/day is recommended. Once the condition