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Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31.

Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.

Author information

  • 1Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address:
  • 2Moscow City Oncology Hospital, Moscow, Russia.
  • 3Department of Medicine, University of Athens, Medical School, Athens, Greece.
  • 4Petrov Research Institute of Oncology, Saint Petersburg, Russia.
  • 5Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
  • 6Royal Marsden Hospital, London, UK.
  • 7Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
  • 8Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France.
  • 9University Hospital Schleswig-Holstein, Kiel, Germany.
  • 10Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France.
  • 11Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy.
  • 12APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France.
  • 13Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
  • 14Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia.
  • 15Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain.
  • 16Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.
  • 17Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 18Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
  • 19University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany.
  • 20Istituto Nazionale Tumori Regina Elena, Rome, Italy.
  • 21Volograd Regional Oncology Dispensary #3, Volzhsky, Russia.
  • 22Elbe Klinikum Stade, Stade, Germany.
  • 23Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine.
  • 24University Hospital Essen, Essen, Germany.
  • 25Mount Vernon Cancer Centre, Northwood, UK.
  • 26Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France.
  • 27David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
  • 28Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
  • 29Merck & Co, Kenilworth, NJ, USA.
  • 30Massachusetts General Hospital Cancer Center, Boston MA, USA.



Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.


We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with, number NCT01584648.


Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group.


The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.



Copyright © 2015 Elsevier Ltd. All rights reserved.

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