Targeted therapy resistance in EGFR-mutant non-small cell lung cancer: Roles of MET, Trop-2-directed antibody–drug conjugates, and molecular monitoring

Abstract

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have substantially improved outcomes in patients with EGFR-mutant non-small cell lung cancer (NSCLC), but acquired resistance remains a major barrier to durable disease control. Objective: This narrative review summarizes the major mechanisms of EGFR-TKI resistance and evaluates the roles of mesenchymal–epithelial transition factor (MET)-targeted therapy, trophoblast cell-surface antigen 2 (Trop-2)-directed antibody–drug conjugates (ADCs), and molecular monitoring in post-resistance management. Methods: Relevant randomized controlled trials, translational studies, and consensus guidelines on targeted therapy resistance in NSCLC were identified from PubMed and Web of Science, with emphasis on recent high-quality evidence and seminal studies. Results: EGFR-TKI resistance arises through on-target EGFR alterations, bypass pathway activation, histologic transformation, and non-genetic adaptation. MET amplification is a clinically relevant bypass mechanism, particularly after third-generation EGFR-TKI exposure, and may support combined EGFR/MET inhibition when confirmed using assay-specific criteria. Trop-2-directed ADCs provide a non-genotype-dependent treatment option for patients with heterogeneous or non-actionable resistance, although Trop-2 expression is not yet a validated universal predictive biomarker. Plasma circulating tumor DNA can facilitate rapid detection of emerging resistance, but negative or discordant plasma findings should be interpreted together with tissue biopsy, disease distribution, and the possibility of histologic transformation. Minimal residual disease assessment remains investigational for treatment-guided decision-making. Conclusion: Post-EGFR-TKI management should follow a mechanism-guided framework integrating progression pattern, tissue and plasma reassessment, biomarker-specific interpretation, matched therapy, and longitudinal molecular monitoring. Prospective studies are needed to standardize testing thresholds and optimize treatment sequencing.