Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options

Simple Summary Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently indicated as first-line therapy in patients with non-small-cell lung cancer (NSCLC) and sensitizing EGFR mutations; as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs; and as adjuvant therapy for patients with early stage, resected NSCLC, harboring EGFR mutations. Understanding the patterns of resistance, including both on-target and off-target mechanisms, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting. Standard therapeutic approaches after progression to osimertinib include other targeted therapies-when a targetable genetic alteration is detected-and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib. The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.