BRAF in non-small cell lung cancer: From molecular mechanisms to clinical practice

Abstract

V-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations are found in up to 4% of patients with non-small cell lung cancer (NSCLC). Approximately 2% of advanced NSCLC cases harbor a BRAF V600E (class I) mutation. Because targeted therapies inhibiting BRAF (e.g., dabrafenib and encorafenib) and MEK (trametinib and binimetinib) are associated with improved outcomes as first- or second-line treatment for BRAF V600E-mutant NSCLC, both European Society for Medical Oncology and National Comprehensive Cancer Network guidelines recommend testing for the BRAF V600E oncogenic driver at the time of diagnosis. In recent years, the treatment landscape of this molecular subgroup has seen great development. Different therapeutic strategies including anti-programmed death ligand 1 antibodies and kinase inhibitors have been assessed thus far, with novel agents (e.g., pan-BRAF inhibitors) and therapeutic associations underway in preclinical and clinical trials. This review describes the current understanding of the BRAF clinicopathologic role in NSCLC, with a special focus on published trials assessing currently approved therapies. Mechanisms of drug resistance and future perspectives on the therapeutic approach of BRAF-deregulated NSCLC are also summarized.

Keywords: BRAF; BRAF V600E mutation; BRAF inhibitors; clinical trials; investigational agents; liquid biopsy; non–small cell lung cancer (NSCLC); resistance mechanisms.