Combined EGFR and MET inhibition in three patients with EGFR-mutant non-small cell lung cancer and pretreatment MET alterations

Abstract Background EGFR tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC), whereas MET pathway activation is a recognized bypass mechanism in acquired resistance. The clinical relevance of pretreatment MET amplification or marked MET protein overexpression is less well defined. Methods We report three older patients (aged 77, 80, and 91 years) with advanced EGFR L858R-mutant NSCLC and pretreatment MET abnormalities. Cases 1 and 2 received first-line aumolertinib monotherapy and experienced early disease progression, with progression-free survival (PFS) of approximately 1.2 and 2.5 months, respectively. Case 3 received first-line pemetrexed plus furmonertinib and second-line pemetrexed plus carboplatin before third-line aumolertinib plus savolitinib in a salvage setting. Results After combined EGFR/MET inhibition with aumolertinib plus savolitinib or glumetinib, all three patients achieved partial responses. Cases 1 and 2 also showed marked improvement in malignant pleural effusions. PFS on dual therapy was 6 months in Case 1, 4 months and ongoing at the reported follow-up in Case 2, and 4 months in Case 3. No grade 3 or higher adverse events were reported. Conclusion In these clinically heterogeneous cases, inadequate disease control before MET-directed treatment was followed by radiographic responses during combined EGFR/MET inhibition. These observations are biologically consistent with MET-mediated bypass signaling and support further prospective evaluation of pretreatment MET dysregulation as a potential modifier of EGFR-TKI sensitivity. The findings are hypothesis-generating and do not establish a predictive biomarker or justify routine upfront dual EGFR/MET inhibition.