Targeting BRAF‐Mutant Non‐Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy

Non‐small cell lung cancer (NSCLC) remains the leading cause of cancer‐related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B‐Raf proto‐oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%–4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen‐activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen‐activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF‐mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF‐mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. IMPLICATIONS FOR PRACTICE. Personalized medicine has begun to provide substantial benefit to patients with oncogene‐driven non‐small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen‐activated protein kinase kinase (MEK) has the potential to change the course of the disease for patients with BRAF‐mutant NSCLC, as it has in BRAF‐mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.