CHICAGO–Vemurafenib, an orally available inhibitor of oncogenic BRAF kinase, is associated with significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated V600EBRAF-mutated metastatic melanoma, an international randomized Phase 3 trial reported during the American Society of Clinical Oncology’s 2011 Annual Meeting has found.

Also known as PLX4032, vemurafenib is the first drug to improve OS when compared with standard chemotherapy and also the first drug to improve PFS and response proportion in this patient population.

Approximately 40% to 60% of melanomas harbor a V600E mutation in the BRAF gene; therefore, it was hypothesized that inhibition of the mutated BRAF kinase may be of clinical benefit. Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues randomized patients with treatment-naïve unresectable stage IIIC/IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test to oral vemurafenib 960mg twice daily (n=337) or IV dacarbazine 1,000mg/m2  IV every 3 weeks (n=338).

“This is really a huge step toward personalized care in melanoma,” said Dr. Chapman. “This is the first successful melanoma treatment tailored to patients who carry a specific gene mutation in their tumor, and could eventually become one of only two drugs available that improves overall survival in advanced cancers.” The other drug, ipilimumab, is an immune therapy.

Randomization was stratified by stage, ECOG performance status (PS), LDH, and geographic region. Patients were assessed for tumor responses after Weeks 6 and 12 and then every 9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included response rate, response duration, and safety. Baseline demographics were similar between the treatment groups.

At the preplanned interim analysis (50% of deaths needed for final analysis), patients who received vemurafenib had an estimated 6-month survival of 84% compared with 64% for dacarbazine (HR 0.37 [0.26-0.55]; P<0.0001) and a 74% decrease in risk of tumor progression ([0.20-0.33]; P<0.0001).

The objective response rate was 48.4% for vemurafenib and 5.5% for dacarbazine. Benefit in OS and PFS was observed in all subgroups examined. As a result of these analyses, patients receiving dacarbazine were recommended to switch to vemurafenib.

Vemurafenib has a manageable safety profile with few drug-related discontinuations. The most common Grade 3 or greater adverse events for vemurafenib vs. dacarbazine were cutaneous squamous cell carcinoma (12% vs. <1%)), rash (8% vs. 0%), increased liver enzymes (7% vs. 1%), and keratoacanthoma (6% vs. 0%).

The investigators concluded that vemurafenib represents a promising new therapy for patients with metastatic V600EBRAF-mutated metastatic melanoma and is a foundation upon which to build combination therapies. A phase I trial has been initiated with vemurafenib and ipilimumab.