Biology and Clinical Management of Non-V600 BRAF Alterations in NSCLC

: BRAF mutations are detected in approximately 3% to 8% of patients with NSCLC. In contrast to melanoma, in which most BRAF mutations occur at the V600 codon, only approximately 35% of BRAF-mutant NSCLC tumors harbor V600 mutations. Among the remaining cases, 60% to 70% present non-V600 mutations, primarily in exons 11 and 15. BRAF mutations are classified into three classes according to their kinase activity and their dependence on RAS activation. Compared with class I (V600), patients with class II and class III mutations are associated with poorer clinical outcomes partly due to the lack of effective targeted therapeutic strategies. Indeed, although dual BRAF and MEK inhibition has demonstrated clinical benefit in BRAF V600-mutant NSCLC, there is currently no consensus on treatment strategies for patients with class II and class III mutations. Beyond point mutations, other BRAF alterations (e.g., gene fusions, deletions, and amplifications) have been identified in treatment-naive tumors and in the context of acquired resistance to targeted therapies in other oncogene-driven NSCLC subtypes. However, the biology and clinical implications of these alterations remain poorly characterized. In this review, we provide a comprehensive overview on the biology, epidemiology, and therapeutic strategies of class II/III BRAF mutations, fusions, deletions, and amplifications in NSCLC. We highlight current challenges in the clinical management of BRAF-mutant NSCLC, emerging inhibitors, and combinatorial therapeutic strategies developed to treat non-V600E BRAF-driven cancers. Finally, we briefly discuss BRAF alterations in the context of resistance to targeted therapies in other oncogene-driven NSCLC.