Targeting MET in EGFR-Mutated NSCLC

MET alterations, mainly gene amplification and protein overexpression, represent a major mechanism of primary and acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated (EGFRm) NSCLC. Both de novo and acquired MET dysregulation can activate downstream oncogenic signaling, providing a strong rationale for dual inhibition of EGFR and MET. This review summarizes the data for targeting MET alterations in EGFRm NSCLC, with emphasis on the clinical relevance of distinguishing MET amplification from c-MET overexpression. We discuss contemporary diagnostic strategies, including tissue-based fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry, and the limitations of circulating tumor DNA (ctDNA) assays. We then review the clinical data supporting EGFR- and MET-directed approaches across the therapeutic classes, including tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Finally, we highlight unresolved challenges including the lack of standardized biomarker thresholds, optimal timing of MET inhibition, and rational sequencing of available agents. As the therapeutic landscape continues to evolve, improved biomarker precision and optimization of treatment strategies will be essential to maximize the benefit of MET-targeted therapies in EGFRm NSCLC.