title: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au.
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authors.initials: GV
authors.lastname: Long
authors.affiliation: Moscow City Oncology Hospital, Moscow, Russia.
authors.forename: Daniil
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authors.lastname: Stroyakovskiy
authors.affiliation: Department of Medicine, University of Athens, Medical School, Athens, Greece.
authors.forename: Helen
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authors.lastname: Gogas
authors.affiliation: Petrov Research Institute of Oncology, Saint Petersburg, Russia.
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authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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authors.affiliation: Royal Marsden Hospital, London, UK.
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authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Claus
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authors.affiliation: Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France.
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authors.affiliation: University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Axel
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authors.affiliation: Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France.
authors.forename: Jean-Jacques
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authors.affiliation: Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy.
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authors.affiliation: APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France.
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authors.affiliation: Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
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authors.affiliation: Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia.
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authors.affiliation: Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain.
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authors.affiliation: Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.
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authors.affiliation: Netherlands Cancer Institute, Amsterdam, Netherlands.
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authors.affiliation: Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Johan
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authors.lastname: Hansson
authors.affiliation: University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jochen
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authors.affiliation: Istituto Nazionale Tumori Regina Elena, Rome, Italy.
authors.forename: Virginia
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authors.forename: Nadezhda
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authors.lastname: Kovalenko
authors.affiliation: Elbe Klinikum Stade, Stade, Germany.
authors.forename: Peter
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authors.affiliation: Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine.
authors.forename: Volodymr
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authors.lastname: Probachai
authors.affiliation: University Hospital Essen, Essen, Germany.
authors.forename: Dirk
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authors.lastname: Schadendorf
authors.affiliation: Mount Vernon Cancer Centre, Northwood, UK.
authors.forename: Paul
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authors.lastname: Nathan
authors.affiliation: Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France.
authors.forename: Caroline
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authors.lastname: Robert
authors.affiliation: David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: DeMarini
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Jhangir G
authors.initials: JG
authors.lastname: Irani
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Suzanne
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authors.lastname: Swann
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Jeffrey J
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authors.lastname: Legos
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Jin
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Bijoyesh
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authors.lastname: Mookerjee
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D010091:Oximes / Q000008:administration & dosage*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage*; D011744:Pyrimidinones / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib