Clinical attributes and outcomes in metastatic non-small cell lung cancer bearing BRAF mutations treated with targeted therapy versus immunotherapy.
Authors: Dawar Richa , Gawri Kunal , Rodriguez Estelamari , Kwon Deukwoo , Basher Fahmin , Costa Philippos Apolinario , Khan Khadeja , Torres Tisdrey , Ikpeazu Chukwuemeka , Lopes Gilberto 
Published: June 2021

e21219

Background: Mutations in BRAF oncogene have been identified in about 2-4% of non-small cell lung cancer (NSCLC) patients. Combination of tyrosine kinase inhibitors (TKI), dabrafenib and trametinib has shown improved and enduring results in both first line and second line setting. Given the rarity of BRAF mutations, and the approval of TKI, the role of Immune Checkpoint Inhibitors (ICI) still needs to be ascertained. Methods: We conducted a retrospective review of 19 BRAF-mutant lung cancer patients from 2013-2020 at the University of Miami. Clinicopathologic features, and patient’s response to chemotherapy/ICI vs anti-BRAF targeted therapy (ABTT) was investigated. Duration of response (DOR) was calculated from the initiation of therapy, and Overall survival (OS) was calculated from the diagnosis of metastatic disease. OS was estimated by Kaplan-Meier method and log-rank test was used to compare groups. Hazard ratio (HR) and corresponding 95% confidence interval were estimated using Cox proportional hazards regression model. All tests were two sided and statistical significance was considered when p<0.05. Results: Total 19 patients with a median age of 63 (range 54-87) were identified from a cohort of 575 sequenced lung cancer patients (prevalence of 3.3%). 6 patients were never-smokers, 13 former/current smokers; 10 were women; 10 were Non-Hispanic White, 8 Hispanic, and 1 African American. Majority had adenocarcinoma (n=17) and non-V600E BRAF mutation (n=13)). PD-L1 expression testing (n=11) was negative in 55% (n=6 of 11), low in 9% (n=1 of 11), and high in 36% (n=4 of 11). All patients presented with metastatic disease; lung (16), bone (7), brain (5), and liver (4). 47.4% (n=9) of patients received platinum-based doublet chemotherapy as first-line (FL) treatment; 21.1% (n=4) received combined chemotherapy+ICI as FL; 5% (n=1) received ABTT as FL. Overall, 47% (n=9) received ABTT; 11.1% (n=1) as FL, 33.3% (n=3) as second line, 44.4% (n=4) as third line, and 11.1% (n=1) as fourth line. Median OS in the entire cohort was 1.86 years (95 % CI :1.26-2.32). Median DOR to ICI as first line or second line agent was 3 months (mos) (range 0.5-25mos). Median DOR to TKI in BRAFV600E cases was 13 mos (range 7-53mos), as second line agent or beyond. Among patients with BRAFV600E mutation, median OS was 4.89 years (95% CI 4.31-NA) in recipients of ABTT, and 1.68 years (95% CI not estimable) in patients who did not receive ABTT. Conclusions: In our BRAF-mutant NSCLC cohort, median DOR was greater in patients treated with ABTT, than those with ICI. ABTT treated BRAFV600E-mutant patients had longer OS, in comparison to those treated without ABTT. Our analysis highlights a potentially significant benefit of ABTT, and an unsatisfactory response with ICI, in patients harboring BRAFV600E mutation; therefore, the role of ICI in this subgroup needs further investigation.