BRAF V600E-mutant non-small-cell lung cancer

BRAF V600E lung cancer was recognised as a targetable subtype after the melanoma experience, in which BRAF inhibitors alone produced responses that were quickly lost through MEK reactivation and paradoxical pathway activation, so combined BRAF and MEK blockade became the rule. In the phase 2 BRF113928 study dabrafenib plus trametinib produced response rates of 64 percent in treatment-naive and 63 percent in previously treated patients with median progression-free survival of about 10 months, and the FDA approved the combination for BRAF V600E lung cancer in June 2017, the first targeted therapy for this driver.

PHAROS (2023) tested encorafenib plus binimetinib in the same population: response rates of 75 percent in 59 treatment-naive and 46 percent in 39 previously treated patients, with fewer of the fevers that interrupt dabrafenib and trametinib, and the combination was approved in October 2023. Both pairs are given until progression; pyrexia, fatigue, nausea, rash and cardiac and eye toxicity are monitored. BRAF V600E lung cancers often express PD-L1 and, unlike EGFR or ALK disease, respond to checkpoint inhibitors, so chemoimmunotherapy is a reasonable alternative first line and the standard afterwards.

Non-V600 BRAF mutations (class II and III), the other half of BRAF-mutant lung cancers, do not respond to BRAF plus MEK inhibitors and are treated as driver-negative disease; MEK inhibitors and pan-RAF inhibitors are in trials for them. Open questions are the sequence of targeted therapy and immunotherapy and how to treat resistance, which usually arises through reactivation of the MAPK pathway.