Osimertinib is currently the preferred first‐line therapy in patients with non‐small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second‐line therapy in T790M‐positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long‐lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre‐treated with osimertinib and its future treatment applications.
