Unveiling BRAF Mutations in Non-small Cell Lung Cancer: State of the Art and Future Perspectives

Abstract

Lung cancer is the most frequently diagnosed malignancy worldwide in recent decades, representing the leading cause of cancer-related mortality globally. Lung cancer is mainly divided into two types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC being the most common, representing about 85% of cases. NSCLC is increasingly recognized to harbor various druggable genetic alterations; among them, activating BRAF mutations are found in approximately 3–4% of NSCLC patients. The objective of this review is to provide a comprehensive overview of the key biological and pathophysiological characteristics of BRAF molecular alterations, their impact on clinical practice, and emerging insights from translational research. We performed a search of the PubMed database on April 22, 2026. A review of retrieved literature related to BRAF mutations and their clinical implications in NSCLC was completed. The Catalogue of Somatic Mutation in Cancer (COSMIC) database and the NCCN-NSCLC Guidelines were evaluated. Functional classification of BRAF genetic alterations, molecular assays for detection of BRAF gene mutation, advancements of targeted therapies and immunotherapy for BRAF‑mutant NSCLC, and treatment resistance mechanisms were described. Several ongoing studies currently evaluating novel agents with broader biological activity and various drug combinations were reported. Emerging strategies—including next-generation MAPK inhibitors, ADCs, and engineered cellular therapies—were discussed, offering promising avenues to enhance efficacy, overcome resistance, and expand therapeutic options for these patients. Despite limited clinical data, particularly in first line and neoadjuvant settings, remain major challenges, addressing critical questions will be useful to optimize the management of BRAF-mutant NSCLC.