Promising benefits of MET inhibition combined with EGFR/ALK tyrosine kinase inhibitor in heavily treated non-small cell lung cancer patients with EGFR-mutant/ALK rearrangement and MET overexpression: a retrospective cohort study.

BACKGROUND: Resistance to epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) remains common in patients with EGFR-mutant or ALK rearrangement non-small cell lung cancer (NSCLC). Mesenchymal-epithelial transition (MET) overexpression plays a key role in acquired resistance. However, real-world evidence on combined tyrosine kinase inhibition targeting both EGFR/ALK drivers and MET is limited. This study aimed to evaluate the efficacy and safety of combined EGFR/ALK and MET inhibition in this population. METHODS: We performed a single-center, retrospective cohort study of NSCLC patients with EGFR mutations or ALK rearrangements who developed resistance to prior EGFR/ALK-targeted therapies and exhibited MET overexpression. Eligible patients received combined treatment with EGFR/ALK TKIs and MET inhibitors. Treatment responses were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: Data of a total of 23 patients were analyzed. The objective response rate (ORR) was 69.6%, with partial responses in 16 patients and stable disease in 6. Median PFS was 6.9 months. High-level MET overexpression, defined as immunohistochemistry (IHC) 3+, was associated with a higher response rate compared to MET IHC 2+. The treatment was generally well-tolerated, with most adverse events being low-grade and manageable. CONCLUSIONS: Dual inhibition of EGFR/ALK and MET offers promising antitumor activity with an acceptable safety profile in EGFR/ALK-mutant NSCLC patients with MET overexpression, providing a viable strategy for overcoming acquired resistance.