Dalmelitinib Plus Aumolertinib in Advanced NSCLC Patients With EGFR-TKI Resistance and MET Amplification: A Randomized Phase 3 Trial

PURPOSE MET amplification accounts for up to 30% of acquired resistance to EGFR-TKI, especially following third-generation EGFR-TKI treatment, yet precision-targeted therapeutic options remain limited. Early-phase studies demonstrated promising antitumor activity with the MET-TKI dalmelitinib combined with the third-generation EGFR-TKI aumolertinib. This phase 3 trial compared dalmelitinib-aumolertinib with platinum-based chemotherapy in EGFR -mutated, MET -amplified advanced NSCLC after EGFR-TKIs progression. PATIENTS AND METHODS This randomized, open-label, phase 3 trial ( NCT06110663 ) enrolled patients with locally advanced or metastatic EGFR -mutated, MET -amplified NSCLC after EGFR-TKI progression. MET amplification was defined by fluorescence in situ hybridization as a mean MET copy number ≥5 or MET / CEP7 ratio ≥2. Patients were randomly assigned (1:1) to dalmelitinib-aumolertinib or platinum-based chemotherapy groups. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review per RECIST 1.1. Secondary endpoints included overall survival, objective response rate (ORR), duration of response (DoR), and safety. RESULTS A total of 314 enrolled patients were assigned to dalmelitinib-aumolertinib (n=156) or platinum-based chemotherapy (n=158). Median follow-up was 11.2 months at the data cutoff date (December 10, 2025). Median PFS was 6.2 months with dalmelitinib-aumolertinib and 4.4 months with chemotherapy (HR, 0.60; 95% CI, 0.45 to 0.81; P <0.001). Corresponding ORRs were 59.6% and 38.6%, and median DoRs were 9.7 months and 4.4 months, respectively. Overall survival data were immature. Grade ≥3 treatment-emergent adverse events occurred in 50.0% and 51.0% of patients, respectively. Toxicity profiles differed, with more hepatic laboratory abnormalities with dalmelitinib-aumolertinib and more hematologic toxicities with chemotherapy. CONCLUSION The dalmelitinib-aumolertinib combination significantly improved PFS versus chemotherapy, with a manageable safety profile in advanced EGFR -mutated, MET -amplified NSCLC after progression on EGFR-TKI. These findings support dual EGFR/ MET inhibition as a new treatment option in this biomarker selected population.