Genomic determinants of resistance to BRAF/MEK inhibitors in BRAF V600E –mutant non–small cell lung cancer.

8647 Background: BRAF V600E mutations occur in approximately 2–3% of non–small cell lung cancer (NSCLC). BRAF/MEK inhibition (BRAFi+MEKi) yields high response rates and durable clinical benefit but acquired resistance is inevitable. BRAFi+MEKi therapy may select for resistant tumor clones, induce secondary genomic alterations, and drive changes in the tumor immunophenotype. However, the landscape of resistance mechanisms to BRAFi+MEKi in NSCLC remains largely unknown. Methods: We conducted a global, multicenter analysis of patients with advanced BRAF V600E–mutant NSCLC treated with BRAFi±MEKi across multiple academic centers and available public datasets. Eligible patients had matched pre- and post-treatment next-generation sequencing (NGS). Analyses were restricted to oncogenic or likely oncogenic alterations per OncoKB and/or ClinVar. Results: Among 33 patients with matched pre- and post– BRAFi±MEKi samples, median age was 66 years; 39.4% were women, 67.7% had a history of tobacco use, and 97.0% had adenocarcinoma at diagnosis. Objective response to BRAFi±MEKi in this cohort was 81.8%, while median progression-free survival was 8 months; only 3 patients (9.1%) had primary resistance. Acquired resistance mechanisms were diverse, encompassing reactivation of the RAS/RAF/ERK signaling pathway (via BRAF -dependent and BRAF -independent mechanisms), activation of alternative bypass pathways (e.g. PI3K/AKT and HIPPO), and alterations associated with cell-cycle dysregulation. Concurrent resistance mechanisms were identified in 12.1% of cases, and one patient developed histologic transformation to small-cell lung cancer (SCLC). No identifiable resistance mechanism was detected in 11 patients (33.3%). The most common acquired genomic alterations were RAS mutations, observed in 21.2% of cases ( NRAS Q61K, n = 1; NRAS Q61R, n = 1; KRAS G12D, n = 1; KRAS G12V, n = 1; KRAS Q61R, n = 1; NRAS Q61R + KRAS 61H, n = 1; KRAS G12V + KRAS Q61H, n = 1), followed by MET amplifications (12.1%, n = 4). Additional acquired events included BRAF kinase-domain duplication, MAP2K1 and NF2 mutations, and FGFR4 amplification. Putative resistance alterations involving DNA damage repair genes (e.g., CHEK2, BRIP1) were also identified. Clinically, one patient with acquired MET amplification showed loss of the MET -amplified clone on liquid biopsy after adding crizotinib to BRAFi+MEKi, without grade≥3 adverse events, suggesting a potentially targetable resistance mechanism with therapeutic implications. Conclusions: Our findings define the genomic landscape of acquired resistance to BRAFi+MEKi in BRAF V600E–mutant NSCLC and highlight the emergence of diverse resistance mechanisms, including SCLC transformation, MET amplification, and RAS mutations, several of which are potentially actionable and may inform rational post-BRAFi/MEKi therapeutic strategies.