New Strategies and Novel Combinations in EGFR TKI-Resistant Non-small Cell Lung Cancer

Osimertinib is the current standard-of-care for the first-line treatment of Epidermal Growth Factor Receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Progression after osimertinib ineluctably occurs, and standard of care treatment options beyond progression have mainly included next-line platinum doublet chemotherapy. With better understanding of the varied molecular mechanisms of resistance to osimertinib, several opportunities for the use of targeted agents are emerging that include MET amplification, observed in 15% of patients, and resistant EGFR mutations, including C797S in 7% of patients. Evidence for the use of targeted therapies in such situations is mostly based on case reports, but clinical trials are being conducted with MET inhibitors, such as amivantamab, an EGFR-MET bispecific antibody, or next-generation EGFR inhibitors, such as patritumab-deruxtecan, a HER3 antibody drug conjugate. In this review, we outline our proposed approach to current clinical practice for patients with EGFR mutant, osimertinib-resistant NSCLC which includes the following potential strategies: - Continuation of osimertinib beyond progression following local ablative treatment of oligoprogressive disease, - Tissue rebiopsy of progressive site and possibly concurrent liquid biopsy to evaluate for mechanism of resistance utilizing comprehensive genomic profiling, -Discussion at a molecular tumor board for assessment for enrollment in clinical trials/expanded access program if available with innovative drugs or possible off-label use of available targeted agents, based on the results of molecular profiling, -If no mechanism of resistance identified, administration of platinum-based chemotherapy with antiangiogenic agents. The role of immunotherapy will also be addressed given the uncertain benefit.