Targeting the BRAF-MEK Pathway in BRAF V600E-Mutant Metastatic NSCLC

The discussion focuses on the unique treatment approach for BRAF V600E–mutant NSCLC, which differs from other oncogenic drivers such as EGFR or ALK that are typically treated with single-agent targeted therapy. In BRAF V600E NSCLC, standard care involves a combination of two targeted agents: a BRAF inhibitor and a MEK inhibitor. This dual approach targets the same signaling pathway at different points, upstream at BRAF and downstream at MEK, leading to improved efficacy compared with BRAF inhibition alone. Early studies with dabrafenib plus trametinib demonstrated superior outcomes over monotherapy, findings that are consistent with experience in melanoma, where BRAF V600E is more common. Importantly, adding an MEK inhibitor may also reduce certain toxicities, including paradoxical pathway activation that can increase the risk of secondary skin malignancies.

This combination strategy is particularly suited to the V600E mutation and may not apply to other BRAF alterations. The conversation then turns to first-line treatment decisions, highlighting ongoing debate between using BRAF-directed therapy versus immunotherapy or chemoimmunotherapy. Although BRAF-mutant tumors may show some immunotherapy sensitivity, emerging data suggest that starting with BRAF-targeted combinations may be optimal, reserving chemoimmunotherapy for later lines, especially given the biological heterogeneity of this patient population.