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Lancet Oncol. 2014 Mar;15(3):323-32. doi: 10.1016/S1470-2045(14)70012-9. Epub 2014 Feb 7.

Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.

Author information

  • 1Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Electronic address:
  • 2Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3Institut Gustave Roussy, Paris, France.
  • 4Royal Marsden Hospital, London, UK.
  • 5The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 6University of Zurich, Zurich, Switzerland.
  • 7Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA.
  • 8Princess Margaret Hospital and University Health Network, Toronto, ON, Canada.
  • 9The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
  • 10Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
  • 11The University of Tübingen, Tübingen, Germany.
  • 12Istituto Europeo di Oncologia, Milan, Italy.
  • 13University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
  • 14University of Manchester, Manchester, UK.
  • 15APHP Oncodermatology, Hôpital Saint Louis University, Paris, France.
  • 16Saint André Hospital, Bordeaux, France.
  • 17University Hospital Essen, Essen, Germany.
  • 18Beverly Hills Cancer Center, Beverly Hills, CA, USA.
  • 19University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 20Gustave-Roussy Cancer Center and University Paris-Sud, Villejuif/Paris Sud, France.
  • 21Nantes University Hospital, Nantes, France.
  • 22Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 23Massachusetts General Hospital, Boston, MA, USA.
  • 24Genentech Inc, San Francisco, CA, USA.
  • 25Roche Molecular Systems Inc, Pleasanton, CA, USA.
  • 26F Hoffmann-La Roche, Basel, Switzerland.
  • 27University of Kiel, Kiel, Germany.



In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups.


Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with, NCT01006980.


675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.


Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation.


F Hoffmann-La Roche-Genentech.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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