BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape

Abstract

In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAF^V600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAF^V600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAF^V600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could potentially overcome issues of resistance and target non-V600E mutations. Therefore, because targeted therapies with enhanced efficacy are on the horizon, being able to identify BRAF mutations in metastatic NSCLC may become even more important.

Fig. 1. BRAF mutation classes and mechanism of actions for BRAF/MEK inhibitors.

Class I and II mutations are RAS-independent, constitutively active monomers (class I) or dimers (class II). Class III mutations are RAS-dependent dimers with compromised kinase activity. Current BRAF inhibitors are effective for class I-mutant monomers. Next-generation RAF inhibitors can inhibit dimers and may inhibit class II and III mutations. P, phosphorylation.

Fig. 2. Timeline of key advancements in the treatment of BRAF^V600E-mutant NSCLC.

Positive data readouts for BRAF-mutant NSCLC (blue) and approved treatments for BRAF^V600E-mutant NSCLC (green) are shown. ^aBRAF inhibitors. ^bMEK inhibitors. ^cIn 2022, dabrafenib plus trametinib was approved for patients with unresectable metastatic BRAF^V600E-mutant solid tumors who progressed on previous treatments and have no acceptable alternative option. ^dImmunotherapy that targets PD-1. ^eImmunotherapy that targets PD-L1.

Fig. 3. Adverse events experienced by ≥10% of patients with BRAF/MEK combination therapies.

a Adverse events (AEs) shown for dabrafenib plus trametinib occurred in at least 10% of patients in combined data from interim analysis of treatment-naive and previously treated patients^,. AEs led to dose reduction, dose interruption, and permanent treatment discontinuation in 37%, 67%, and 16% of patients. ^aChest pain includes musculoskeletal chest pain. b Treatment-related AEs (TRAEs) shown for encorafenib plus binimetinib occurred in at least 10% of patients. TRAEs led to dose reduction, dose interruption, and permanent treatment discontinuation in 24%, 44%, and 15% of patients. Comparisons of safety profiles should be done cautiously since data are from different trials and reported as all-causality AEs for one treatment combination and as TRAEs for the other combination. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, CNS central nervous system, CPK creatine phosphokinase.