Ongoing Progress in BRAF-Mutated Non–Small Cell Lung Cancer

Activating BRAF mutations are detected in 1.5% to 4.5% of patients with non–small cell lung cancer (NSCLC). These mutations involve the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, and affect proliferation, differentiation, transcriptional regulation, and survival of cancer cells. Today, the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib is the preferred first-line treatment option in patients with advanced BRAF V600–mutated NSCLC, with an objective response rate of 64%, a median progression-free survival of 10.2 months, a median overall survival of 24.6 months, and a median duration of response of 10.4 months, according to a pivotal phase 2 study. These outcomes remain inferior to those achieved with other targeted therapies in advanced NSCLC with other driver alterations. First-generation BRAF inhibitors are not active in the class II and III BRAF mutations that form the other half of BRAF mutations in NSCLC. New RAF inhibitors are being investigated in early trials. Novel treatment combinations, particularly with immune checkpoint inhibitors, are also underway. Patient referral to expert centers and enrollment in basket trials as well as serial tissue and liquid biopsies are needed to improve the understanding and the treatment outcomes of this relatively rare disease subset.