Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma.

Melanoma/Skin Cancers
Session Type and Session Title: 
Plenary Session, Plenary Session including Science of Oncology Award and Lecture
Abstract Number: 


J Clin Oncol 29: 2011 (suppl; abstr LBA4)
P. B. Chapman, A. Hauschild, C. Robert, J. M. G. Larkin, J. B. A. G. Haanen, A. Ribas, D. Hogg, S. O'Day, P. A. Ascierto, A. Testori, P. Lorigan, R. Dummer, J. A. Sosman, C. Garbe, R. J. Lee, K. B. Nolop, B. Nelson, J. Hou, K. T. Flaherty, G. A. McArthur; Memorial Sloan-Kettering Cancer Center, New York, NY; Universitaetsklinikum Schleswig-Holstein, Kiel Schleswig-Holstein, Germany; Cancer Institute Gustave Roussy, Villejuif, France; Urology Unit, Royal Marsden Hospital, London, United Kingdom; The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA; Department of Medical Oncology, Princess Margaret Hospital and University of Toronto, Toronto, ON, Canada; The Angeles Clinic and Research Institute, Los Angeles, CA; Istituto Nazionale Tumori, Naples, Italy; European Institute of Oncology, Milan, Italy; The Christie Hospital, Manchester, United Kingdom; University Hospital of Zurich, Zurich, Switzerland; Vanderbilt University Medical Center, Nashville, TN; University of Tübingen, Tübingen, Germany; Pharma Research & Early Development, Hoffmann-La Roche Inc., Nutley, NJ; Plexxikon Inc., Berkeley, CA; Genentech Inc., South San Francisco, CA; Massachusetts General Hospital, Boston, MA; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

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Abstract Disclosures


Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in V600EBRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation. Methods: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. Results: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. Conclusions: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, V600EBRAF-mutated metastatic melanoma.