Efficacy and Safety of BRAF Inhibitors With or Without MEK Inhibitors in BRAF-Mutant Advanced Non-Small-Cell Lung Cancer: Findings From a Real-Life Cohort

Little is known regarding the performance of BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitor (MEKi) combination in the real-life setting. A real-life cohort of BRAF-mutant (BRAFm) non-small-cell lung cancer (NSCLC) patients (n = 58) was analyzed, focusing on comparative efficacy and safety of BRAFi and BRAFi + MEKi combination. In V600E BRAFm NSCLC, BRAFi + MEKi are effective, well tolerated, and superior to BRAFi. Non-V600E kinase-active BRAFm NSCLC may respond to BRAFi + MEKi. Background: Real-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non-small-cell lung cancer (NSCLC) is lacking. Patients and Methods: Consecutive BRAFm advanced NSCLC patients (n = 58) treated in 9 Israeli centers in 2009-2018 were identified. These were divided according to mutation subtype and treatment into groups A1 (V600E, BRAFi; n = 5), A2 (V600E, BRAFi + MEKi; n = 15), A3 (V600E, no BRAFi; n = 7), B1 (non-V600E, BRAFi +/- MEKi; n = 7), and B2 (non-V600E, no BRAFi; n = 23); one patient received both BRAFi and BRAFi + MEKi. Safety, objective response rate, progression-free survival with BRAFi +/- MEKi, and overall survival were assessed. Results: Objective response rate was 40%, 67%, and 33% in groups A1, A2, and B1, respectively (P =.5 for comparison between groups A1 and A2). In group B1, G469A and L597R mutations were associated with response to BRAFi + MEKi. Median progression-free survival was 1.2 months (95% confidence interval [ CI], 0.5-5.3), 5.5 months (95% CI, 0.7-9.3), and 3.6 months (95% CI, 1.5-6.7) for groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P =.04). Median overall survival with BRAFi +/- MEKi was 1.7 months (95% CI, 0.5-NR), 9.5 months (95% CI, 0.2-14.9), and 7.1 months (95% CI, 1.8-NR) in groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .6). Safety profiles differed slightly, and similar treatment discontinuation rates were observed with BRAFi and BRAFi + MEKi. Conclusion: In the real-life setting, activity and safety of BRAFi + MEKi in V600E BRAFm NSCLC are comparable to those observed in prospective clinical trials; the combination of BRAFi + MEKi is superior to monotherapy with a BRAFi. Further research should be done to explore the impact of BRAFi + MEKi treatment on the natural history of BRAFm NSCLC. (C) 2019 Elsevier Inc. All rights reserved.