Recent advances in EGFR-targeted therapies for non-small cell lung cancer

INTRODUCTION: The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies. AREAS COVERED: This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease - specifically TKI combinations with chemotherapy (FLAURA2) or bispecific antibodies (MARIPOSA) - and emerging post-progression strategies to overcome acquired resistance mechanisms. A comprehensive literature search (January 2021-March 2026) was conducted via PubMed, and recent major oncology conference proceedings (ASCO, ESMO, WCLC, ELCC) and clinical trial registries for ongoing studies. EXPERT OPINION: The therapeutic landscape is shifting from a uniform frontline TKI monotherapy approach toward biomarker-driven, risk-stratified, intensification. High-risk patients (e.g. TP53 co-mutations, L858R) derive significant benefit from combination regimens, whereas mono-TKI remains appropriate for favorable prognostic subgroups. Future progress relies on validating predictive biomarkers - particularly circulating tumor DNA (ctDNA) dynamics - to guide adaptive treatment strategies, balancing efficacy gains against toxicity and costs, while ensuring equitable global access to novel therapies.