Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC - mechanisms and evolving treatment approaches.

Resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major obstacle in the clinical management of EGFR-mutant non-small-cell lung cancer (NSCLC). Despite the transformative therapeutic activity of the multiple iterations of EGFR TKIs, spanning from first-generation reversible inhibitors such as erlotinib and gefitinib to the current standard-of-care third-generation covalent inhibitor osimertinib, primary or acquired resistance to these agents inevitably emerges via diverse mechanisms. The advent of combination therapies that incorporate chemotherapy, anti-angiogenic agents, bispecific antibodies or antibody-drug conjugates has increased clinical benefit but introduced new resistance phenotypes, underscoring the dynamic plasticity and complexity of tumour evolution under therapeutic pressure. In this Review, we provide a comprehensive synthesis of the molecular mechanisms that underlie resistance to third-generation EGFR TKIs, describe biomarker-guided and biomarker-unselected therapeutic strategies to overcome these mechanisms, and discuss emerging approaches to pre-empt resistance through early application of combination therapies. We highlight the paradigm shift from radiological to molecular monitoring of resistance to therapy and explore how advances in circulating tumour DNA analysis, artificial intelligence and multi-omics might facilitate adaptive treatment strategies. As the therapeutic landscape evolves, a more complete mechanistic understanding of resistance will be essential to guide rational treatment sequencing, inform trial design and improve long-term outcomes for patients with EGFR-mutant NSCLC.