Co-occurring Genomic Alterations and Association With Progression-Free Survival in BRAF^V600-Mutated Nonmelanoma Tumors

BRAF^V600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration–approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy. To identify whether co-occurring genomic alterations drive resistance to BRAF-targeted therapies, we analyzed next-generation sequencing data from 30 advanced BRAF-mutated nonmelanoma cancers treated with BRAF inhibitor monotherapy. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. All statistical tests were two-sided. We identified a strong association between co-occurring PI3K-mTOR pathway aberrations and primary resistance to BRAF-targeted therapy. PI3K-mTOR pathway aberrations were associated with a statistically significant reduction in progression-free survival (HR = 15.0, 95% CI = 3.6 to 63.0, P < .001) and overall survival (HR = 19.2, 95% CI = 3.7 to 100.0, P < .001). This suggests that co-occurring genomic alterations may predict response and resistance to BRAF inhibitor therapy and identify subgroups of BRAF-mutated nonmelanomas cancers.