Synergistic antitumor effects of combination therapy with MET TKI vabametkib and a third-generation EGFR TKI lazertinib in MET-amplified EGFR-mutant NSCLC

The in vivo efficacy was evaluated using two patient-derived xenograft (PDX) models (YHIM-1035(1) and YHIM-1053), characterized for MET amplification by whole-exome sequencing or droplet digital polymerase chain reaction (ddPCR). In vitro studies demonstrated that vabametkib plus lazertinib potently inhibited EGFR/MET phosphorylation at the nanomolar level, leading to the suppression of PI3K/AKT and MAPK signaling pathways and subsequent down-regulation.

Consistently, in vivo studies revealed that vabametkib plus lazertinib significantly suppressed the growth of MET-dependent xenograft tumors, while in certain models, monotherapy also exhibited strong antitumor effects. These findings suggest that the combination of the MET TKI vabametkib and the third-generation EGFR TKI lazertinib represent a promising therapeutic strategy to overcome acquired EGFR TKI resistance in patients with MET-amplified NSCLC, potentially guiding future clinical applications.