Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial

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.

Conflict of interest statement

Declaration of interests DP reports advisory role for Novartis, Pfizer, Roche, Boehinger, Lilly, Bristol-Myers Squibb, AstraZeneca, MSD and Pierre Fabre. GR reports grants from GlaxoSmithKline and Novartis; consulting with Novartis; and employer receives research funding from Pfizer, Chugai/Roche and Millennium for support of research led by him. FB reports personal fees from GlaxoSmithKline and Novartis. P-J Souquet reports clinical trial for GlaxoSmithKline. HJMG reports payments to his institution from Roche, MSD, Pfizer and GlaxoSmithKline. LP at the time of the study, was an employee of GlaxoSmithKline. CN reports employment at GlaxoSmithKline at the time the study was conducted, former employment at Novartis and current employment at GlaxoSmithKline. B. Ma reports employment at GlaxoSmithKline at the time the study was conducted. AD, at the time of the study, was an employee of GlaxoSmithKline, is now an employee of Novartis. B Mookerjee, at the time of the study, was an employee of GlaxoSmithKline, is now an employee of Novartis; and owns stock in GlaxoSmithKline and Novartis. CMC was an employee of Novartis and GlaxoSmithKline. BEJ reports personal fees from AstraZeneca, Clovis Oncology, Novartis, Merck, Genentech; honoraria from Chugai Pharmaceuticals; received shares of post-market revenue for EGFR Genotyping patent. TMK, JM, EQ, EFS, RJK, BCC, and MAS report nothing to disclose.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile

Figure 2. Response to dabrafenib in BRAF V600E–mutant NSCLC

Maximum change in the sum of lesion diameters by best confirmed response in ≥ second-line patients treated with dabrafenib (N = 78) at the time of the clinical activity analyses. The dashed line at 20 represents the RECIST 1.1 definition for progressive disease, while the dashed line at −30 represents the definition for partial response. Asterisks represent patients with no change from baseline at the time of assessment. NE denotes not estimable, NSCLC non-small cell lung cancer, PD progressive disease, PR partial response, RECIST Response Evaluation Criteria In Solid Tumors, SD stable disease.

Figure 3. Duration of investigator-assessed response in ≥ second-line patients at time of mature activity analyses

Duration of response in patients with one prior therapy (purple bars) or ≥ two prior therapies (yellow bars). Arrows indicate patients remaining on therapy. Asterisks represent patients censored/lost to follow-up.