HUTCHMED announced that a New Drug Application (NDA) has been submitted to the US Food and Drug Administration (FDA) for ORPATHYS (savolitinib) plus TAGRISSO (osimertinib). The submission was made by its partner AstraZeneca. It covers patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have MET overexpression or amplification. These patients progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI). HUTCHMED described the combination as a biomarker-directed, all-oral, chemotherapy-free option.
A Resistance Problem Without a Targeted Answer
The filing addresses a gap that has persisted since third-generation EGFR TKIs became standard care. These drugs have significantly improved outcomes in EGFR-mutated NSCLC, but tumors eventually find ways around them. MET overexpression or amplification is among the most common resistance mechanisms, and it is associated with poor prognosis. HUTCHMED estimates that about 34% of tumors develop high MET levels after progression on a third-generation EGFR TKI.
The population is large. Lung cancer accounts for almost one in four cancer deaths worldwide, and 80-85% of patients have NSCLC. About 75% of NSCLC patients are diagnosed with advanced disease. EGFR mutations are found in roughly 10-15% of NSCLC patients in the US and Europe and 30-40% in Asia.
Inside SAFFRON
SAFFRON is a randomized, open-label, global Phase 3 trial of 338 patients with EGFR-mutated, locally advanced or metastatic NSCLC and MET overexpression or amplification. Their disease had progressed after first- or second-line osimertinib. The trial ran at 230 centers in 29 countries across North America, Europe, South America and Asia. It compared savolitinib 300 mg twice daily added to osimertinib 80 mg once daily against doublet platinum-based chemotherapy.
PFS is the primary endpoint and OS is a key secondary endpoint. The companies report statistically significant and clinically meaningful improvements in both, with a safety profile consistent with each drug’s known profile and no new safety concerns. HUTCHMED calls SAFFRON the first global Phase 3 trial to show significant PFS and OS benefits in this setting. Numerical results have not been released and will come at ESMO.
One design feature stands out. Patients were prospectively selected using the high MET cut-offs identified in the earlier Phase 2 SAVANNAH trial, which measured MET status with two tests: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).
A Second Phase 3 Trial Also Heads to ESMO
SAFFRON is not the only savolitinib-osimertinib study going to Madrid. HUTCHMED’s ESMO preview said results from the China-based SANOVO Phase 3 trial will be presented in a Proffered Paper session. SANOVO tested the combination in previously untreated patients with EGFR-mutated, MET-overexpressing NSCLC in China. Topline results reported on August 31 showed a statistically significant PFS improvement and a clinically meaningful OS benefit versus osimertinib alone. SAFFRON’s topline results were reported on August 17. HUTCHMED to present 2 lung cancer studies at ESMO 2026.
SANOVO: Osimertinib Plus Savolitinib Moves MET-Directed Therapy Into First-Line EGFR-Mutated NSCLC
Together, the two trials cover different points on the treatment timeline: first-line therapy in SANOVO and post-osimertinib progression in SAFFRON.
Where the Combination Stands Today
Savolitinib is jointly developed by AstraZeneca and HUTCHMED and commercialized by AstraZeneca. In China, the combination is approved for EGFR mutation-positive non-squamous NSCLC with MET amplification after progression on EGFR TKI therapy, based on the SACHI Phase 3 trial. Switzerland has granted temporary authorization for EGFR-mutated NSCLC with high MET overexpression or amplification after osimertinib, based on SAVANNAH. In the US, both drugs are established separately. Osimertinib is approved as monotherapy in more than 120 countries, including the US, and in combination with chemotherapy in more than 80. The savolitinib combination itself has not yet been reviewed by the FDA.
Johnny Cheng, HUTCHMED’s Acting CEO and CFO, called the filing an important step toward potentially bringing the combination to US patients. He said the SAFFRON result reflects the long-standing HUTCHMED-AstraZeneca collaboration in MET-driven progression.
What Comes Next
A submission is not an approval, and the release gives no FDA decision timeline. The next milestone is ESMO 2026 in Madrid, October 23-27. There, SAFFRON’s numbers will show how large the survival benefit is, and how it compares with the chemotherapy patients receive after progression on osimertinib today.
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