David Planchard1, Tae Min Kim2, Julien Mazieres3, Elisabeth Quoix4, Gregory Riely5, Fabrice Barlesi6, Pierre-Jean Souquet7, Egbert F Smit8, Harry J M Groen9, Ronan J Kelly10, B C Cho11, Mark A Socinski12, Lini Pandite13, Christine Nase14, Bo Ma15, Anthony D'Amelio16, Bijoyesh Mookerjee17, C Martin Curtis18, Bruce E Johnson19. 1. Department of Medical Oncology, Gustave Roussy, Villejuif, France. 2. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 3. Thoracic Oncology Unit, Rangueil-Larrey Hospital, Toulouse, France; Paul Sabatier University, Toulouse, France. 4. Pneumology Department, University Hospital of Strasbourg, Strasbourg, France. 5. 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. 6. Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Livon, Marseille, France. 7. Acute Respiratory Medicine and Thoracic Oncology Department, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. 8. Department of Pulmonary Diseases, Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands. 9. Department of Pulmonary Diseases, University of Groningen, Groningen, Netherlands; University Medical Center Groningen, Groningen, Netherlands. 10. Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. 11. College of Medicine, Yonsei University, Seoul, South Korea. 12. Lung Cancer Section, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. 13. Adaptimmune LLC, Philadelphia, PA, USA. 14. GlaxoSmithKline, Collegeville, Pennsylvania, PA, USA. 15. Biothera, Eagan, MN, USA. 16. Novartis Pharmaceuticals, King of Prussia, PA, USA. 17. Novartis Pharmaceuticals, East Hanover, NJ, USA. 18. Novartis Pharmaceuticals, Morrisville, NC, USA. 19. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: Bruce_Johnson@dfci.harvard.edu.
Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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%). INTERPRETATION: 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. FUNDING: GlaxoSmithKline.
BACKGROUND: 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. METHODS: 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. FINDINGS: 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%). INTERPRETATION: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. FUNDING: GlaxoSmithKline.
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