Detailed characterization of combination treatment with MET inhibitor plus EGFR inhibitor in EGFR-mutant and MET-amplified non-small cell lung cancer.

Background: Detailed clinical data about combination treatment with MET inhibitor (METi) and EGFR inhibitor (EGFRi) is lacking in patients with EGFR-mutant, MET-amplified, and EGFRi-resistant non-small cell lung cancer (NSCLC). This study aimed to report longitudinal data on the efficacy and safety of this combination treatment.

Methods: We retrospectively analyzed 44 patients with advanced EGFR-mutant and MET-amplified NSCLC who were treated with any types of METi plus EGFRi after progression with EGFRi at the National Cancer Center Hospital. Longitudinal clinicogenomic data and plasma circulating tumor DNA (ctDNA) data were collected.

Results: The overall response rate was 74.4% and median progression-free survival (PFS) was 5.3 months [95% confidence interval (CI): 3.3-7.3]. Twenty-three patients (52.3%) required either or both treatment discontinuation due to adverse effects. The main cause of discontinuation was pneumonitis (69.2%). There was no significant difference in the PFS of patients with or without METi discontinuation [hazard ratio (HR), 0.93; 95% CI: 0.49-1.78; P=0.83]. Median clearance time of MET amplification in plasma ctDNA was measured as 63 days. Patients who stopped METi within 63 days of initiation showed poorer PFS compared to those who discontinued after (HR, 2.78; 95% CI: 1.00-7.75; P=0.050). Diverse resistance mechanisms including on-target mutations in MET (D1246H) and EGFR (C797S or T790M) were detected in 14 patients. One MET D1246H-mutant case and one EGFR C797S-mutant case responded to sitravatinib and amivantamab, respectively.

Conclusions: A combination of METi and EGFRi showed a promising anti-tumor effect in advanced EGFR-mutant and MET-amplified NSCLC. Pneumonitis was the main adverse effects leading to treatment discontinuation. Early discontinuation of METi negatively affected the survival outcomes.