The emerging role of antibody-drug conjugates in EGFR-mutant non-small cell lung cancer with acquired resistance to third-generation EGFR tyrosine kinase inhibitors

Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a significant clinical challenge for patients with advanced EGFR-mutant non-small cell lung cancer. Resistance arises through diverse mechanisms, including on-target and off-target gene alterations and histologic transformation. Notably, in up to 50% of cases, the etiology of resistance remains unknown, underscoring the need for effective non-targeted systemic therapies. In recent years, multiple antibody-drug conjugates (ADCs) have been developed and evaluated in this setting, with trophoblast cell-surface antigen 2 ADCs recently receiving approval from the National Medical Products Administration and the Food and Drug Administration for use after EGFR-TKI resistance. This review comprehensively outlines the structural features of ADCs, clinical trial designs involving biomarker-selected and unselected patient populations, and the application of ADCs in clinical practice including novel combination strategies such as chemotherapy plus amivantamab or ivonescimab. Toxicity management is also summarized. Finally, the review discusses key challenges and future directions in ADC development across four aspects: optimizing ADC design through artificial intelligence and multi-omics; evaluating novel combination therapies; evolving from overcoming resistance to delaying or preventing resistance to third-generation EGFR-TKIs via patient selection and circulating tumor DNA guidance; and advancing personalized toxicity management.