Characterization of BRAF fusions and their therapeutic and resistance implications in NSCLC

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.