BRAF fusions define therapeutic vulnerability and tyrosine kinase inhibitor resistance in non-small cell lung cancer.

BACKGROUND

BRAF fusions are rare but clinically relevant oncogenic events in non-small cell lung cancer (NSCLC), yet their molecular characteristics and optimal management remain unclear.

METHODS

We retrospectively analyzed 97 patients with NSCLC harboring kinase domain-retaining BRAF fusions, stratified into de novo (N = 43) and acquired (N = 54) groups. Clinical and genomic features were compared across subgroups and comparator driver cohorts.

RESULTS

We identified 104 BRAF fusions involving 53 unique partner genes, 29 of which were novel. Common partners included AGK (12.5%), IGR (11.5%), ZC3HAV1 (7.7%), TRIM24 (5.8%), and MKRN1 (5.8%). IGR and DTNB were more commonly observed in de novo cases, whereas AGK-BRAF fusions predominated in acquired cases. Among de novo cases, 65.1% lacked co-occurring drivers. ZNF703 mutations and NRF2 pathway alterations were recurrently enriched in BRAF fusion-only tumors, while CTNNB1 and NKX2-1 mutations were enriched versus ALK-rearranged cases. BRAF fusions co-occurring with other drivers showed enrichment of KMT2C and RTK-RAS pathway mutations, with TP53 mutations enriched compared to RET-rearranged tumors. One patient with TRIM24-BRAF and EGFR exon 19 deletion derived clinical benefit from dual MEK and EGFR inhibition. Acquired BRAF fusions were frequently detected after EGFR-TKI therapy, representing the predominant alteration in 63.0% of cases. 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. These findings support repeated comprehensive genomic profiling at progression and suggest that pathway-directed combinations, such as MEK plus EGFR inhibition, may offer individualized treatment options for selected patients.