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.

Abstract

Introduction: The ORCHARD (NCT03944772) study was conducted to characterize resistance mechanisms and identify optimal treatments following progressive disease (PD) on first-line osimertinib. We report results from the osimertinib plus savolitinib module.

Methods: Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (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 endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DoR) and overall survival (OS), and safety. Correlation of ORR with baseline molecular alterations was an exploratory analysis.

Results: Thirty-two patients were enrolled; all had tumors with MET amplification. At primary analysis cutoff (January 2023), confirmed ORR was 47% (80% confidence interval [CI]: 35-60). Median DoR was 14.5 months (95% CI: 5.6-18.7). Median PFS was 7.6 months (95% CI: 3.2-15.9). There was a trend towards increased ORR in patients with high MET gene copy number (≥10 versus <10). Fourteen patients (44%) had grade ≥3 treatment-emergent adverse events; most commonly pneumonia (n = 3; 9%). At final database lock (May 2024), 20 patients (63%) had died; median OS 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 following PD on first-line osimertinib. Safety was consistent with profiles of the individual drugs.