Tailored strategies to overcome third-generation TKI resistance in EGFR-mutated non-small cell lung cancer

INTRODUCTION: In the era of precision medicine, targeting resistance mechanisms is a rational approach to optimize treatment management based on tumor molecular profiling, with the goal of improving clinical outcomes. However, the role of tailored strategies in the treatment algorithm of EGFR-mutated NSCLC remains incompletely defined. AREAS COVERED: This review provides an overview of resistance mechanisms to EGFR-targeted therapy. Acquired resistances include on-target alterations (EGFR C797S and other secondary kinase domain mutations), off-target pathways activation (MET or HER2 amplification, RAS-MAPK, oncogenic fusions), and neuroendocrine transformation to SCLC. Evidence from clinical and observational studies demonstrates activity of tailored therapies, such as EGFR plus MET inhibitors combinations. In parallel, mechanism-agnostic strategies, including bispecific antibodies and ADC have emerged as effective options in the post-osimertinib setting. EXPERT OPINION: Comprehensive molecular assessment through both tissue and liquid biopsy at EGFR-TKI progression is essential to identify actionable alterations and guide treatment decisions. When supported by Molecular Tumor Board discussion, biomarker-driven strategies could enable personalized treatment selection and provide effective chemotherapy-free options. Emergence of upfront combinations is reshaping the biological landscape of EGFR-TKI resistance, increasing the proportion of patients with unknown escape mechanisms and potentially affecting the feasibility of molecularly matched therapies in later lines.