Osimertinib Plus Savolitinib in Patients With EGFR-Mutated Advanced NSCLC With MET Alterations After First-Line...

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• The ORCHARD study investigated resistance mechanisms and optimal treatments for EGFR-mutated NSCLC following progression on first-line osimertinib.
• This report focuses on the osimertinib plus savolitinib treatment module within the ORCHARD study.

Purpose of the Study:

• To evaluate the efficacy and safety of combining osimertinib with savolitinib in patients with EGFR-mutated NSCLC who experienced disease progression on first-line osimertinib.
• To characterize resistance mechanisms and identify optimal subsequent treatments.

Main Methods:

• Patients with EGFR-mutated NSCLC and MET amplification (≥4 copies) after progression on first-line osimertinib received osimertinib plus savolitinib.
• The primary endpoint was investigator-assessed objective response rate (ORR); secondary endpoints included progression-free survival, duration of response, overall survival, and safety.
• Next-generation sequencing of post-progression biopsies was used to identify MET gene amplification.

Main Results:

• Of 32 enrolled patients with MET amplification, the confirmed ORR was 47% (80% CI: 34-60).
• Median duration of response was 14.5 months (95% CI: 5.6-18.7), and median progression-free survival was 7.6 months (95% CI: 3.2-15.9).
• Grade 3 or higher treatment-emergent adverse events occurred in 44% of patients, most commonly pneumonia (9%). Median overall survival was 20.7 months (95% CI: 9.9-34.8).

Conclusions:

• Osimertinib plus savolitinib demonstrated encouraging clinical benefit in EGFR-mutated advanced NSCLC patients with MET amplification post-progression on first-line osimertinib.
• The safety profile of the combination was consistent with the known profiles of the individual agents.