Acquired Resistance Mechanisms to Osimertinib: The Constant Battle

Lung cancer is the leading cause of cancer-related mortality worldwide. Detectable driver mutations have now changed the course of lung cancer treatment with the emergence of targeted therapy as a novel strategy that widely improved lung cancer prognosis, especially in metastatic patients. Osimertinib (AZD9291) is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat stage IV EGFR-mutated non-small-cell lung cancer. It was initially designed to target both EGFR-activating mutations and the EGFR T790M mutation as well, which is the most common resistance mechanism to first- and second-generation EGFR-TKIs. Following the FLAURA trial, osimertinib is now widely used in the first-line setting. However, resistance to osimertinib inevitably develops, with numerous mechanisms leading to its resistance, classified into two main categories: EGFR-dependent and EGFR-independent mechanisms. While EGFR-dependent mechanisms consist mainly of the C797S EGFR mutation, EGFR-independent mechanisms include bypass pathways, oncogenic fusions, and phenotypic transformation, among others. This review summarizes the molecular resistance mechanisms to osimertinib, with the aim of identifying novel therapeutic approaches to overcome osimertinib resistance and improve patient outcome.