Abstract 2519: Characterization of BRAF fusions and their therapeutic and resistance implications in NSCLC

Abstract Background: BRAF fusions are rare but clinically relevant oncogenic events in non-small cell lung cancer (NSCLC). Their molecular characteristics and optimal management remain incompletely understood. Methods: We retrospectively analyzed 97 NSCLC patients harboring kinase domain-retaining BRAF fusions, stratified as de novo (N=43) or acquired (N=54). Genomic and clinical features were compared between subgroups and against other oncogenic driver cohorts. Results: We identified 104 BRAF fusions involving 53 unique 5’ partners, 29 of which were novel. Frequent partners included AGK (12.5%), IGR (11.5%), ZC3HAV1 (7.7%), TRIM24 (5.8%), and MKRN1 (5.8%). IGR- and DTNB-BRAF fusions were enriched in de novo cases, while AGK-BRAF predominated in the acquired setting. Among de novo cases, 65.1% lacked co-occurring drivers. ZNF703 mutations and NRF2 pathway alterations were recurrent in BRAF fusion-only tumors, whereas CTNNB1 and NKX2-1 mutations were enriched relative to ALK-rearranged cases. BRAF fusions co-occurring with other drivers showed enrichment of KMT2C and RTK-RAS pathway mutations, and TP53 mutations were more frequent compared to RET-rearranged tumors. One patient harboring TRIM24-BRAF and EGFR exon 19 deletion achieved clinical benefit from combined MEK and EGFR inhibition. Acquired BRAF fusions predominantly emerged after EGFR-TKI therapy (63.0%), consistent with a role in treatment resistance. Median progression-free survival on prior EGFR-TKIs aligned with clinical trial benchmarks. Conclusions: BRAF fusions in NSCLC are molecularly heterogeneous, with distinct genomic landscapes between de novo and acquired cases. Their frequent emergence post-EGFR-TKI highlights a key resistance mechanism and supports comprehensive genomic profiling to guide individualized therapy. Citation Format: Kai Wang, Chao Yi, Xiong Ning, Dalin Xiong, Song Wang, Xiaoying Wu, Hua Bao, Haimeng Tang, Xue Wu, Yuan Jiang, Hongyu Deng, Faqing Tang. Characterization of BRAF fusions and their therapeutic and resistance implications in NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2519.