title: Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial.
abstract: Activating BRAF(V600E) (Val600Glu) mutations are found in about 1-2% of lung adenocarcinomas, which might provide an opportunity for targeted treatment in these patients. Dabrafenib is an oral selective inhibitor of BRAF kinase. We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer (NSCLC) positive for the BRAF(V600E) mutation.
  
  
  
  In this phase 2, multicentre, non-randomised, open-label study, we enrolled previously treated and untreated patients with stage IV metastatic BRAF(V600E)-positive NSCLC. Patients received oral dabrafenib 150 mg twice daily. The primary endpoint was investigator-assessed overall response, which was assessed in patients who had received at least one dose of dabrafenib; safety was also assessed in this population. The study is ongoing but not enrolling patients in this cohort. This trial is registered with ClinicalTrials.gov, number NCT01336634.
  
  
  
  Between Aug 3, 2011, and Feb 25, 2014, 84 patients were enrolled, six of whom had not previously received systemic treatment for NSCLC. 26 of the 78 previously treated patients achieved an investigator-assessed overall response (33% [95% CI 23-45]). Four of the six previously untreated patients had an objective response. One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten (12%), asthenia in four (5%), and basal-cell carcinoma in four (5%).
  
  
  
  Dabrafenib showed clinical activity in BRAF(V600E)-positive NSCLC. Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options.
  
  
  
  GlaxoSmithKline.
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Planchard
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Thoracic Oncology Unit, Rangueil-Larrey Hospital, Toulouse, France; Paul Sabatier University, Toulouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Pneumology Department, University Hospital of Strasbourg, Strasbourg, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Quoix
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Joan and Sanfor I Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Riely
authors.affiliation: Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Livon, Marseille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.affiliation: Acute Respiratory Medicine and Thoracic Oncology Department, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Souquet
authors.affiliation: Department of Pulmonary Diseases, Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Department of Pulmonary Diseases, University of Groningen, Groningen, Netherlands; University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.affiliation: Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
authors.affiliation: College of Medicine, Yonsei University, Seoul, South Korea.
authors.forename: B C
authors.initials: BC
authors.lastname: Cho
authors.affiliation: Lung Cancer Section, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.affiliation: Adaptimmune LLC, Philadelphia, PA, USA.
authors.forename: Lini
authors.initials: L
authors.lastname: Pandite
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, PA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Nase
authors.affiliation: Biothera, Eagan, MN, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.affiliation: Novartis Pharmaceuticals, King of Prussia, PA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: D'Amelio
authors.affiliation: Novartis Pharmaceuticals, East Hanover, NJ, USA.
authors.forename: Bijoyesh
authors.initials: B
authors.lastname: Mookerjee
authors.affiliation: Novartis Pharmaceuticals, Morrisville, NC, USA.
authors.forename: C Martin
authors.initials: CM
authors.lastname: Curtis
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: Bruce_Johnson@dfci.harvard.edu.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010091:Oximes / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib