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Novel Agents Revolutionize Melanoma Treatment

Emma Hitt, PhD
Published Online: Thursday, September 5, 2013
The mechanism of action of vemurafenib
(Zelboraf) in inhibiting BRAF activity.

The mechanism of action of vemurafenib (Zelboraf) in inhibiting BRAF activity.

Until recently, the cornerstone of therapy for metastatic melanoma had been chemotherapy with dacarbazine (DTIC) and immunotherapy with high-dose interleukin-2 (HD IL-2) or interferon-α (IFN-α). Although considered standard-of-care treatment, DTIC has shown objective response rates as low as 15.3% for a total of 3356 patients enrolled in more than 20 studies. Additionally, most of these responses were partial. Despite significant toxicity, immunotherapy with highdose IL-2 resulted in a substantial benefit for some patients, leading to a 27% survival rate at 2 years and 16% at 4 years, in a trial involving 684 patients. However, the efficacy of IFN-α remains controversial. Its significant toxicity, especially at high doses, has restricted its use. Due to its easier use and reduced side effects compared with unmodified IFN-α, pegylated IFN-α was approved by the FDA in the adjuvant setting in 2011 for patients with lymph node-positive resected melanoma. Trials remain ongoing to evaluate its optimal dosage, as well as the subset of patients that might benefit from this option.1

Frontline treatment options for patients with advanced melanoma have recently improved with the 2011 FDA approval of vemurafenib and ipilimumab, both with indications for metastatic disease. Vemurafenib is an orally available, targeted agent that selectively inhibits the BRAF kinase. It has specificity for the V600E-mutated form of the protein, the oncogenically active variant in 90% of patients with BRAF-mutated melanoma.2 In the randomized phase III BRIM-3 study,vemurafenib was compared with DTIC in 675 patients with previously treated, BRAFV600E-positive metastatic melanoma. The response rate was substantially improved in patients treated with vemurafenib versus DTIC (48% vs 5%). Patients in the vemurafenib arm also experienced a markedly improved 6-month overall survival (OS) compared with those in the DTIC arm (84% vs 64%). Vemurafenib was also associated with a relative reduction in risk of death (63%), and a 74% reduction in the risk of either death or disease progression compared with DTIC (P< .001).3,4

Ipilimumab is a fully human, monoclonal antibody directed against the T-cell antigen cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). In a multicenter, singlearm, phase II clinical trial, ipilimumab was shown to be active in patients with relapsed metastatic melanoma, with 27% of patients achieving disease control, despite a low overall response rate (5.8%). The 1-year and 2-year survival rates were 47.2% and 32.8%, respectively.5

Subsequently, in the randomized, prospective phase III MDX010-20 trial, ipilimumab significantly prolonged median OS when administered either as a single-agent (10.1 months) or combined with the gp100 vaccine (10.0 months), versus gp100 alone (6.4 months; P = .003 and P < .001 for each comparison, respectively).6 Another phase III trial, Study 024, found that OS was significantly improved in patients in the DTIC plus ipilimumab combination group (11.2 vs 9.1 months; P <.001). Survival rates were higher in the ipilimumab–DTIC group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%). Treatment with ipilimumab plus DTIC produced a two-fold improvement in the median duration of response compared with the DTIC plus placebo arm (19.3 vs 8.1 months; P = .03).7 Both vemurafenib and ipilimumab are recommended by the National Comprehensive Cancer Network (NCCN) as category 1 options for treatment of advanced melanoma. The choice of treatment is individualized: Since patients with less-aggressive, low-volume, or asymptomatic metastatic melanoma may have more time to allow an antitumor immune response to mount, they may be good candidates for ipilimumab therapy; patients with more-aggressive, BRAF mutation-positive advanced melanoma, however, may benefit more from first-line treatment with vemurafenib.8

Recent Approvals

In late May 2013, dabrafenib, a BRAF inhibitor, received approval for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation. A multicenter, international, open-label, randomized, active- controlled phase III trial evaluated the efficacy and safety of dabrafenib compared with DTIC in 250 patients with previously untreated, histologically confirmed, unresectable stage 3 or 4 melanoma that has been determined to be BRAFV600E mutation-positive by centralized testing. Median progression-free survival (PFS) was significantly improved in patients in the dabrafenib arm compared to the DTIC arm (5.1 vs 2.7 months). The most common drug-related adverse events (AEs) were hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. Serious AEs involved development of new primary skin cancers (cutaneous squamous cell carcinomas [SCC], new primary melanomas, and keratoacanseen thomas), febrile drug reactions requiring hospitalization, hyperglycemia, and uveitis/iritis.9

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