Savolitinib Plus Osimertinib Improves PFS, OS in MET-Driven NSCLC

Savolitinib (Orpathys) plus osimertinib (Tagrisso) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) vs platinum-based doublet chemotherapy in patients with EGFR-mutated (EGFRm) non–small cell lung cancer (NSCLC) in the phase 3 SAFFRON trial (NCT05261399).¹

Patients enrolled in SAFFRON had locally advanced or metastatic EGFRm NSCLC with high levels of MET overexpression and/or amplification and had progressed on prior treatment with osimertinib. HUTCHMED, the sponsor, said both the PFS and OS end points reached statistical significance but did not disclose hazard ratios, confidence intervals, or P values in the release; detailed findings are expected to be presented at a forthcoming medical meeting and submitted to global regulatory authorities.

Study Design

SAFFRON is a randomized, open-label, multicenter, global phase 3 trial that compared savolitinib (300 mg twice daily) added to osimertinib (80 mg once daily) with platinum-based doublet chemotherapy in 338 patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease progressed following first- or second-line treatment with osimertinib.^1,2 The trial enrolled across 230 centers in 29 countries, including sites in North America, Europe, South America, and Asia. The primary end point is PFS, with OS and objective response rate as key secondary end points.

Patients were prospectively selected for MET overexpression or amplification using the high-level cut-offs identified in the phase 2 SAVANNAH trial (NCT03778229), in which MET status was determined by immunohistochemistry and fluorescence in situ hybridization.¹ The safety profile of savolitinib plus osimertinib in SAFFRON was consistent with the known profiles of each agent individually, and no new safety findings were identified.

Clinical Context and Limitations

Third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib have improved outcomes for patients with EGFRm NSCLC, but an estimated 34% of tumors develop high levels of MET overexpression or amplification after progression on a third-generation EGFR TKI, one of the most common resistance mechanisms in this setting.¹ MET-driven resistance is associated with poor prognosis, and biomarker-directed treatment options that are oral and well tolerated have been limited.

The savolitinib/osimertinib combination previously demonstrated efficacy in the phase 3 SACHI trial (NCT05015608), which supported its approval in China in June 2025 for patients with EGFRm NSCLC and MET amplification after progression on EGFR TKI therapy. The combination also received a temporary authorization in Switzerland based on SAVANNAH data. HUTCHMED and AstraZeneca said the SAFFRON results provide evidence to support global regulatory filings for the combination.

“These exciting results from SAFFRON represent a critical advance for patients with [EGFRmNSCLC] experiencing MET-driven resistance after osimertinib, a population with poor outcomes and no biomarker-directed treatment options available that are oral and well-tolerated. MET is one of the most common drivers of progression on targeted therapy in this setting, and these data underscore the potential impact of this novel osimertinib plus savolitinib combination and the urgency of MET testing to inform treatment decisions,” said Shun Lu, MD, director, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, and principal investigator of the SAFFRON trial, in a news release.

REFERENCES

1. HUTCHMED Announces ORPATHYS® Plus TAGRISSO® Demonstrated Statistically Significant and Clinically Meaningful Improvements in Progression-Free and Overall Survival in MET-Driven EGFR-Mutated Lung Cancer After Progression on TAGRISSO®. News release. HUTCHMED (China) Limited. August 17, 2026. Accessed August 17, 2026. https://www.hutch-med.com/saffron-global-phase-3-readout/

2. Savolitinib plus osimertinib versus platinum-based doublet chemotherapy in participants with non-small cell lung cancer who have progressed on osimertinib treatment (SAFFRON). ClinicalTrials.gov. Accessed August 17, 2026. https://clinicaltrials.gov/study/NCT05261399