Overcoming EGFR-TKI Resistance in EGFR-Mutant Lung Adenocarcinoma

EGFR-targeted therapy has substantially improved the management of EGFR-mutant lung adenocarcinoma (LUAD), but acquired resistance remains a major limitation to durable disease control. Resistance can arise through secondary alterations within EGFR or through mechanisms that reduce tumour dependence on EGFR signalling, and these two situations require fundamentally different therapeutic approaches. This review considers the evolution of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the context of these resistance mechanisms. T790M illustrates resistance caused by altered drug-target interactions, whereas C797S compromises the covalent binding mechanism of third-generation inhibitors. In parallel, MET amplification, HER2 activation and epithelial-mesenchymal transition (EMT) provide alternative routes for maintaining tumour cell survival despite EGFR blockade. Recent therapeutic development has therefore expanded beyond successive generations of EGFR-TKIs. Fourth-generation inhibitors are being designed to address resistant EGFR genotypes, while EGFR/MET bispecific antibodies and MET-directed antibody–drug conjugates (ADCs) seek to exploit bypass signalling or receptor expression as alternative vulnerabilities. However, most of these approaches remain under clinical evaluation, and treatment selection will depend increasingly on accurate identification of the resistance state present in an individual tumour. Future progress is likely to rely on serial molecular monitoring and treatment strategies that can adapt to tumour evolution.