Savolitinib Combo Improves PFS, OS in EGFR-Mutated NSCLC Trial

Combining savolitinib (Orpathys) with osimertinib (Tagrisso) significantly improved progression-free survival (PFS) and overall survival (OS) vs chemotherapy among patients with MET-driven EGFR-mutated non–small cell lung cancer (NSCLC), according to a press release on findings from the phase 3 SAFFRON trial (NCT05261399).¹

What did data from the SAFFRON trial show?

According to the press release, the SAFFRON trial is the first phase 3 study to demonstrate significant improvements in PFS and OS in this treatment setting among patients with tumors of high levels of MET overexpression or amplification who had previously progressed on prior therapy with osimertinib. Additionally, the safety profile of savolitinib plus osimertinib in the SAFFRON trial was comparable with previous reports of each agent; investigators observed no new safety signals.

Investigators plan to highlight detailed findings from the trial at a future medical meeting and share results with global regulatory health authorities. Currently, savolitinib plus osimertinib is approved in China for patients with locally advanced or metastatic NSCLC harboring EGFR mutations and MET amplification following disease progression on prior EGFR tyrosine kinase inhibitor (TKI) therapy.

“These exciting results from SAFFRON represent a critical advance for patients with EGFR-mutated [NSCLC] experiencing MET-driven resistance after osimertinib, a population with poor outcomes and no biomarker-directed treatment options available that are oral and well-tolerated,” principal investigator Shun Lu, a professor and director of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, stated in the press release.¹ “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.”

How was the SAFFRON trial designed?

Although third-generation EGFR TKIs have significantly improved outcomes among those with EGFR-mutated NSCLC, the press release noted that 1 in 3 patients will develop MET overexpression or amplification in their tumors, a common mechanism of resistance. MET-driven resistance correlates with poor prognosis, creating a significant unmet need for effective and well-tolerated regimens in later-line settings.

As part of addressing this gap, investigators designed the open-label, multi-center, international phase 3 SAFFRON trial to assess savolitinib at 300 mg twice daily plus osimertinib at 80 mg once daily vs doublet platinum-containing chemotherapy among 338 patients with EGFR-mutated NSCLC and MET overexpression or amplification following progression on first-line or second-line osimertinib. The trial’s primary end point was PFS. Secondary end points included OS, objective response rate, central nervous system PFS, disease control rate, and duration of response.²

Patients 18 to 130 years old with histologically or cytologically confirmed locally advanced or metastatic NSCLC not amenable to curative therapy, at least 1 documented EGFR mutation, and measurable disease per RECIST v1.1 guidelines were eligible for enrollment on the trial. Other eligibility criteria included having adequate hematological, liver, renal, and cardiac functions as well as an ECOG performance status of 0 or 1.

Those with predominant squamous NSCLC, prior or current treatment with a third-generation EFFR TKI besides osimertinib, and spinal cord compression or brain metastases were ineligible for study entry.

In November 2025, developers announced that the SAFFRON trial completed enrollment.³

“These data demonstrate the clear benefit of adding [savolitinib] to backbone therapy [osimertinib] to address MET overexpression or amplification while maintaining EGFR suppression. By combining [savolitinib] and [osimertinib], with its established efficacy, safety profile and central nervous system protection, we aim to deliver the first biomarker-directed, all-oral option in this setting to patients across the globe,” Susan Galbraith, executive vice president of Oncology Hematology Research & Development at AstraZeneca, concluded.¹

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 Limited. News release. August 17, 2026. Accessed August 17, 2026. https://tinyurl.com/mr2b5ufw
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. Updated August 6, 2026. Accessed August 17, 2026. https://tinyurl.com/5awekv6e
3. HUTCHMED announces enrollment completed of SAFFRON global phase III Trial of ORPATHYS® and TAGRISSO® combination for certain lung cancer patients with MET overexpression and/or amplification after progression on TAGRISSO®. News release. HUTCHMED Limited. November 5, 2025. Accessed August 17, 2026. https://tinyurl.com/2r8kd7j4