Background: Activating BRAFV600E (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 BRAFV600E mutation. Methods: In this phase 2, multicentre, non-randomised, open-label study, we enrolled previously treated and untreated patients with stage IV metastatic BRAFV600E-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 BRAFV600E-positive NSCLC. Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options. Funding: GlaxoSmithKline.
Bibliographical noteFunding Information:
The funder was involved in the design of the study, data collection, data analysis, data interpretation, and writing of the report. Editorial support that did not involve writing was provided by ArticulateScience and funded by the sponsor. LP, CN, BMa, AD'A, BMo, and CMC had access to all the data in the study and the corresponding author had final responsibility for the decision to submit for publication.
DP acts as an adviser for AstraZeneca, Boerhinger Ingelheim, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, and Roche. GR has received grants from GlaxoSmithKline and Novartis, acts as a consultant to Novartis and has received funding for research via his employer from Chugai/Roche, Millennium, and Pfizer. FB has received personal fees from GlaxoSmithKline and Novartis. P-JS has been involved in a clinical trial for GlaxoSmithKline. HJMG's institution has received payments from GlaxoSmithKline, MSD, Pfizer, and Roche. LP, CN, BMa, AD'A, BMo, and CMC were employees of GlaxoSmithKline during the study. CN, AD'A, and BMo have been or are currently employees of Novartis, and BMo owns stock in GlaxoSmithKline and Novartis. BEJ has received personal fees from AstraZeneca, Clovis Oncology, Genentech, Merck, and Novartis, honoraria from Chugai, and shares of post-market revenue for an EGFR genotyping patent. The other authors declare no competing interests.
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