Abstract:Osimertinib, as a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has significantly improved survival outcomes in patients with advanced non-small cell lung cancer harboring EGFR mutations. However, tumor cells can develop acquired resistance through multiple mechanisms, including EGFR dependent mutations, bypass pathway activation, histological transformation, and tumor microenvironment alterations, leading to therapeutic failure. Current clinical strategies show limited efficacy and are challenged by toxicity and tumor heterogeneity. This review systematically outlines the key mechanisms of osimertinib resistance and highlights the potential of emerging technologies such as dynamic liquid biopsy monitoring, nanodrug delivery systems, physiologically based pharmacokinetic modeling, and multiomics predictive integration in reversing or delaying resistance. Moving forward, the integration of realtime molecular monitoring, precise drug delivery, and computationally guided individualized therapy is expected to establish proactive clinical management pathways, thereby improving survival and quality of life for patients with osimertinib resistance.