Dabrafenib in Patients with Braf V600E-Mutant Advanced Non-Small Cell Lung Cancer (Nsclc): a Multicenter, Open-Label, Phase Ii Trial (Brf113928)

Abstract

ABSTRACT Aim: Activating BRAF V600E mutations in NSCLC are present in ≈1.5% of tumors, primarily adenocarcinomas, offering an opportunity to test targeted therapy for this disease. Methods: This single-arm, 2-stage design, Phase II study (NCT01336634) enrolled Stage IV BRAF V600E-mutant NSCLC patients (pts) determined by local laboratory testing. Pts received dabrafenib 150 mg twice daily. Primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1. Results: As of 30 April 2014, 84 pts (female 52%, median age 66 years [range 28–89], ECOG 0–1 86%, Asian 21%, never-smoker 37%, adenocarcinoma histology 96%) were enrolled from August 2011. Median duration on treatment was 4.3 months (range, 0.3–25.2) with 21 (25%) pts still on treatment. Six pts had not received any prior regimen for metastatic disease (first-line pts), 40 pts had one line and 38 pts had received ≥2 lines (range 2–9). ORR for 78 pts with ≥ one line of prior therapy (second-line plus pts) was 32% (n = 25, all partial responses [PRs]; 95% confidence interval [CI] 22–44%) and disease control rate (DCR) for >12 weeks was 56% (95% CI 45–68%), median duration of response (mDoR) was 11.8 months (95% CI 5.4–not reached) with 48% of responders progressed. Based on assessment by independent review committee (IRC), 64 second-line plus pts had measurable disease; ORR and DCR were 28% (n = 18; 95% CI 18–41%) and 52% (95% CI 39–64%) respectively, and mDoR has not been reached. Among the six first-line pts, three pts had PR, four pts had measurable disease based on IRC with three PRs. Most common (>25%) adverse events (AEs) were pyrexia (36%), asthenia (30%), hyperkeratosis (30%), decreased appetite (29%), nausea (27%), cough (26%), fatigue (26%) and skin papilloma (26%). Cutaneous squamous-cell carcinomas, including keratoacanthoma, were reported in 18%. Grade ≥3 AEs occurred in 45% with one event of grade 5 haemorrhage intracranial. Conclusions: Treatment of BRAF V600E mutated advanced NSCLC pts with dabrafenib demonstrated significant antitumor activity with durable objective responses and acceptable safety profile. Dabrafenib is the first drug of its class to show activity in a prospective trial of NSCLC with BRAF mutations. Disclosure: D. Planchard: has received personal fees for participating in advisory boards from AstraZeneca, BI, Lilly, Novartis, Pfizer, Roche and BMS; E. Quoix: has received honoraria for inclusion of patients into study from GSK; G.J. Riely: G.J.R.'s institution received a grant from GSK. G.J.R. received personal fees from Daiichi, Novartis and Abbott for consulting; F. Barlesi: has received a grant and personal fees from GSK; M.A. Socinski: received clinical trial support from GSK; C. Tucker: is an employee of GSK. C.T. owns stock in GSK; B. Ma: is an employee of GSK; B. Mookerjee: is an employee of GSK. B.M. owns stocks in Incyte Corporation and AstraZeneca; C.M. Curtis, Jr: is an employee of GSK. C.M.C.Jr owns stock in GSK; B.E. Johnson: has received personal fees from Roche/Genentech for being an expert witness; Roche/Genentech manufacture a competitor of dabrafenib (vemurafenib). B.E.J. has received personal fees from KEW Group for consultancy.All other authors have declared no conflicts of interest.