Characteristics of and Treatment Strategies for Advanced EGFR-Mutant NSCLC With Concomitant BRAF Variations

BRAF variants were reported resistant mechanisms to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant NSCLC. Nevertheless, characteristics and subsequent treatment strategies of such patients remain unclear.

From October 2016 to May 2020, patients with advanced NSCLC for whom next-generation sequencing detected mutations of both BRAF and EGFR were retrospectively included. From June 2020 to January 2021, patients with EGFR-mutant NSCLC who acquired the BRAF V600E mutation after progression on osimertinib were prospectively enrolled to explore the efficacy and safety of EGFR plus BARF co-inhibition.

A total of 58 patients were retrospectively identified and five prospectively included. BRAF variants were acquired after a median time of 22.7 months from initial diagnosis. The frequency of variations in TP53, PIK3CA, RB1, MET, LRP1B, APC, CDKN2A, MYC, ERBB2, and SMAD4 was all more than 10%; these mutations affected the cell cycle or p53 pathway and the EGFR downstream and bypass pathways. The median progression-free survival was 5.0 months for patients on chemotherapy and 2.1 months for those on TKIs not targeting both of EGFR and BRAF (p = 0.019). The median PFS was 7.8 months in five patients who received EGFR plus BRAF co-inhibitory drugs. RAS signaling was activated on disease progression.

Variations in the EGFR downstream and bypass pathways were frequent in patients with dual mutations of EGFR and BRAF. The efficacies of TKIs not targeting both EGFR and BRAF were inferior to chemotherapy. EGFR plus BRAF co-inhibition improved efficacy. Such treatment strategies should be further explored.