Osimertinib Plus Savolitinib in Patients With EGFR-Mutated Advanced NSCLC With MET Alterations After First-Line Osimertinib: Clinical Outcomes, Safety, and Biomarker Analysis: A Brief Report

INTRODUCTION: The ORCHARD (NCT03944772) study was conducted to characterize resistance mechanisms and identify optimal treatments after progressive disease (PD) on first-line osimertinib. We report results from the osimertinib plus savolitinib module. METHODS: Patients with EGFR-mutated NSCLC with PD on first-line osimertinib with MET gene amplification (≥4 copies of MET over tumor ploidy) per next-generation sequencing of a post-progression biopsy received osimertinib plus savolitinib. Primary end point was investigator-assessed objective response rate (ORR). Secondary end points included progression-free survival, duration of response, overall survival, and safety. Correlation of ORR with baseline molecular alterations was an exploratory analysis. RESULTS: A total of 32 patients were enrolled; all had tumors with MET amplification. At primary analysis cutoff (January 2023), confirmed ORR was 47% (80% confidence interval [CI]: 34-60). Median duration of response was 14.5 months (95% CI: 5.6-18.7). Median progression-free survival was 7.6 months (95% CI: 3.2-15.9). There was a trend toward increased ORR in patients with high MET gene copy number (≥10 versus <10). Furthermore, 14 patients (44%) had grade 3 or higher treatment-emergent adverse events; most often pneumonia (n = 3; 9%). At final database lock (May 2024), 20 patients (63%) had died; median overall survival was 20.7 months (95% CI: 9.9-34.8). CONCLUSIONS: Osimertinib plus savolitinib demonstrated encouraging clinical benefit in patients with EGFR-mutated advanced NSCLC and MET amplification after PD on first-line osimertinib. Safety was consistent with profiles of the individual drugs.