Osimertinib in EGFR-mutated non-small cell lung cancer: a comprehensive narrative review of clinical evidence

Abstract

Osimertinib, a third-generation, mutant-selective, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has fundamentally reshaped the treatment landscape of EGFR-mutated non-small cell lung cancer (NSCLC). Originally approved for T790M-positive disease after progression on earlier-generation tyrosine kinase inhibitors (TKIs), osimertinib has since become the standard-of-care first-line therapy for advanced EGFR exon 19 deletion/L858R-positive NSCLC and the first targeted adjuvant therapy in resected early-stage disease. Its superior systemic efficacy, favorable safety profile, and exceptional central nervous system (CNS) penetration distinguish it from all predecessor agents. However, inevitably acquired resistance, driven by heterogeneous on-target tertiary EGFR mutations, off-target bypass pathway activation, and histological transformation, remains the principal clinical challenge. The postosimertinib treatment era is now being shaped by mesenchymal-epithelial transition factor (MET)-targeted combinations, antibody-drug conjugates, EGFR-MET bispecific antibodies, fourth-generation EGFR TKIs, and frontline intensification strategies. This review synthesizes the current evidence on the clinical indications of osimertinib, efficacy and CNS control, resistance mechanisms and their line-dependent patterns, postprogression management algorithms, combination strategies, guideline evolution, and future directions, providing a comprehensive framework for clinical decision-making and research prioritization.

Keywords

Osimertinib / EGFR mutation / non-small cell lung cancer / resistance mechanisms / CNS metastases / adjuvant therapy / combination therapy / liquid biopsy

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