Background: Vemurafenib is an oral, small-molecule kinase inhibitor that selectively targets activated BRAF V600E and has been approved for the treatment of advanced BRAF mutation-positive melanoma.

Objective: This article reviews the clinical pharmacology, efficacy, tolerability, and pharmacokinetics of vemurafenib and in addition outlines proposed mechanisms of vemurafenib resistance.

Methods: A literature search of MEDLINE and ScienceVerse Scopus was performed using the key words malignant melanoma, BRAF, vemurafenib, and PLX4032. Scientific abstracts, US Food and Drug Administration Web site data (www.accessdata.fda.gov), the manufacturer-submitted approval data from ClinicalTrials.gov (www.clinicaltrials.gov), and the references from applicable publications were also consulted.

Results: Clinical studies have reported that vemurafenib is efficacious and acceptably well-tolerated. In a Phase I study (BRIM-1), a 960-mg BID dose achieved an objective response rate of 81% among 32 patients with melanoma who carried a BRAF V600E mutation. Of the 26 responders, 2 achieved a complete response and 24 a partial response. In BRIM-2, 132 BRAF V600E-positive patients achieved an overall response rate of 53% (95% CI, 44%-62%); 6% achieved a complete response and 47%, a partial response. Response was noted at 6 weeks and lasted a median of 6.7 months (95% CI, 5.6-8.6). Median survival was 15.9 months (95% CI, 11.6-18.3); 77% of patients survived to 6 months (95% CI, 70-85) and 58% to 12 months (95% CI, 11.6-18.3), and an estimated 43% were expected to survive to 18 months (95% CI, 33-53). The Phase III study (BRIM-3) compared vemurafenib to dacarbazine. The hazard ratio (HR) for death with vemurafenib was 0.37 (95% CI, 0.26-0.55; P < 0.001). At 6 months, overall survival was 84% (95% CI, 78-89) versus 64% (95% CI, 56-73) in the vemurafenib and dacarbazine treatment arms, respectively. The HR for tumor progression in the vemurafenib cohort was 0.26 (95% CI, 0.20-0.33; P < 0.001), and the estimated median progression-free survival was 5.3 months with vemurafenib versus 1.6 months with dacarbazine. Finally, the difference in response rates was significant (48% vs 5%, respectively; P < 0.001). The most common adverse events reported have been arthralgia, rash, photosensitivity, fatigue, pruritus, alopecia, cutaneous squamous cell carcinoma, diarrhea, and mild to moderate nausea.

Conclusions: Vemurafenib is effective for advanced melanomas expressing the BRAF V600E mutations. Resistance to BRAF inhibition can be problematic, but new evidence suggests that combination therapy may attenuate the issue. Targeting the cellular activity of melanoma cells is reported to be efficacious and is expected to delay progression and prolong survival.