The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications

SIMPLE SUMMARY: In non-small cell lung cancer that has spread to other locations in the body, identifying genetic abnormalities in a patient’s cancer has allowed for the development of targeted treatments. For cancers that have genetic changes in epidermal growth factor receptor (EGFR), treatments such as osimertinib have allowed patients to live longer. However, these cancers do eventually continue to grow after targeted therapy. In this paper, we aimed to summarize the current research identifying changes in the mesenchymal-epithelial transition (MET) gene that occur after EGFR-targeted therapy, allowing the cancer to become resistant. We summarized current medications that target MET, and early findings from trials that used medications targeting both EGFR and MET together. Targeting both mechanisms at the same time could be a promising new treatment strategy, and larger trials studying these treatments in combination are currently ongoing to understand the potential benefit to patients. ABSTRACT: Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly prolong progression-free survival and overall survival, and are the current standard of care. However, progression after EGFR inhibition invariably occurs, and further study has helped elucidate mechanisms of resistance. Abnormalities in the mesenchymal-epithelial transition (MET) oncogenic pathway have been implicated as common alterations after progression, with MET amplification as one of the most frequent mechanisms. Multiple drugs with inhibitory activity against MET, including TKIs, antibodies, and antibody–drug conjugates, have been developed and studied in advanced NSCLC. Combining MET and EGFR is a promising treatment strategy for patients found to have a MET-driven resistance mechanism. Combination TKI therapy and EGFR-MET bispecific antibodies have shown promising anti-tumor activity in early clinical trials. Future study including ongoing large-scale trials of combination EGFR-MET inhibition will help clarify if targeting this mechanism behind EGFR resistance will have meaningful clinical benefit for patients with advanced EGFR-mutated NSCLC.