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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: georgina.long@sydney.edu.au.
  • 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.

Abstract

BACKGROUND:

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.

METHODS:

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 ClinicalTrials.gov, number NCT01584648.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

GlaxoSmithKline.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID:
26037941
[PubMed - indexed for MEDLINE]
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