• Jeffrey A Sosman, Kevin B Kim, Lynn Schuchter, Rene Gonzalez, Anna C Pavlick, Jeffrey S Weber, Grant A McArthur, Thomas E Hutson, Stergios J Moschos, Keith T Flaherty, Peter Hersey, Richard Kefford, Donald Lawrence, Igor Puzanov, Karl D Lewis, Ravi K Amaravadi, Bartosz Chmielowski, H Jeffrey Lawrence, Yu Shyr, Fei Ye, Jiang Li, Keith B Nolop, Richard J Lee, Andrew K Joe, and Antoni Ribas.
• Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu
• N. Engl. J. Med. 2012 Feb 23; 366 (8): 707-14.

BackgroundApproximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial.MethodsWe designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point.ResultsA total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients.ConclusionsVemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).

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