INTRODUCTION
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
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