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

Introduction: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2022 The Authors.)