HUTCHMED’s Savolitinib-Tagrisso Combo Delivers Positive Phase 3 Results in MET-Driven EGFR-Mutated NSCLC

HUTCHMED has announced positive topline results from the global Phase 3 SAFFRON trial, showing that the combination of ORPATHYS® (savolitinib) and TAGRISSO® (osimertinib) delivered statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) compared with platinum-based doublet chemotherapy in patients with EGFR-mutated non-small cell lung cancer (NSCLC) whose tumors harbor high levels of MET overexpression or amplification and whose disease progressed following treatment with TAGRISSO.

The results represent an important milestone for the HUTCHMED-AstraZeneca collaboration and could pave the way for global regulatory submissions of the combination in this biomarker-defined population.

According to HUTCHMED’s announcement, SAFFRON is the first global Phase 3 trial to demonstrate significant benefits in both PFS and OS in this treatment setting.

Positive Results in a High-Unmet-Need Population

SAFFRON evaluated savolitinib, a selective oral MET tyrosine kinase inhibitor (TKI), in combination with osimertinib, a third-generation EGFR TKI, in patients with EGFR-mutated, locally advanced or metastatic NSCLC whose tumors had high levels of MET overexpression or amplification after progression on TAGRISSO.

The randomized, open-label Phase 3 study enrolled 338 patients across 230 sites in 29 countries, spanning North America, Europe, South America and Asia. Patients were randomized to receive either savolitinib plus osimertinib or platinum-based doublet chemotherapy.

The primary endpoint was PFS, while OS and objective response rate were among the key secondary endpoints. (AstraZeneca)

The positive findings are particularly significant because MET overexpression and amplification are recognized mechanisms of resistance to EGFR-targeted therapy. AstraZeneca estimates that approximately 34% of tumors develop high levels of MET overexpression or amplification after progression on a third-generation EGFR TKI. (AstraZeneca)

For these patients, treatment options following progression on osimertinib remain limited, creating a substantial need for biomarker-directed therapies.

Both PFS and OS Improved

HUTCHMED and AstraZeneca have not yet disclosed detailed hazard ratios, median survival times or response-rate data from SAFFRON. The companies said the full dataset will be presented at a forthcoming medical meeting and submitted to global regulatory authorities.

Nevertheless, the simultaneous achievement of statistically significant improvements in both PFS and OS is notable.

The companies said the findings reinforce the potential of continuing osimertinib as the EGFR-targeted backbone while adding MET inhibition to address a key mechanism of acquired resistance.

“By combining Orpathys and Tagrisso, 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,” said Susan Galbraith, Executive Vice President, Oncology Haematology R&D at AstraZeneca. (AstraZeneca)

Safety Profile Consistent With Known Risks

The safety profile of the combination was consistent with the established safety profiles of savolitinib and osimertinib, with no new safety findings reported, according to the companies.

The safety results are particularly relevant given the potential advantages of an all-oral targeted regimen over conventional chemotherapy in patients who have already progressed following EGFR-directed treatment.

Detailed safety data, including rates of treatment-related adverse events and treatment discontinuations, are expected to be disclosed when the complete SAFFRON dataset is presented at a medical congress.

SAFFRON Builds on Positive SACHI Results in China

The global SAFFRON results build on the success of the SACHI Phase 3 trial, which supported regulatory approval of the savolitinib-osimertinib combination in China in June 2025.

In SACHI, the combination demonstrated a significant improvement in PFS compared with platinum-based chemotherapy. Previously reported results showed median PFS of 8.2 months versus 4.5 months in the overall intent-to-treat population, corresponding to a hazard ratio of 0.34 (P<0.0001). Among patients previously treated with a third-generation EGFR TKI, median PFS was 6.9 months versus 3.0 months, with a hazard ratio of 0.32 (P<0.0001). (Hutch Med)

More mature SACHI data also showed a median OS of approximately 22.9 months for the savolitinib-osimertinib combination versus 17.7 months for chemotherapy in the overall population, although the OS analysis was initially immature. (Hutch Med)

The China approval therefore provided an important proof of concept for targeting MET-driven resistance with savolitinib while maintaining EGFR suppression with osimertinib.

SAFFRON now provides global Phase 3 evidence in a broader international population and could substantially strengthen the regulatory case for the combination outside China.

Potential First Global Biomarker-Directed All-Oral Option

Savolitinib is an oral, highly selective MET inhibitor designed to block aberrant MET signaling caused by MET amplification, overexpression or other activating alterations. Osimertinib selectively targets mutant EGFR and has become a cornerstone of EGFR-mutated NSCLC treatment.

The therapeutic rationale behind the combination is straightforward: continue suppressing EGFR with osimertinib while simultaneously inhibiting MET, a pathway that can emerge as a mechanism of resistance.

Earlier results from the Phase 2 SAVANNAH study helped establish the biomarker strategy used in SAFFRON. Patients were prospectively selected for high levels of MET alteration using IHC and FISH testing. (AstraZeneca)

The companies believe this approach could ultimately establish a new treatment paradigm for patients whose EGFR-mutated tumors develop MET-driven resistance after osimertinib.

Global Regulatory Filings Could Follow

With SAFFRON meeting its key efficacy objectives, HUTCHMED and AstraZeneca are expected to advance discussions with regulatory authorities worldwide.

HUTCHMED CEO and Chief Scientific Officer Weiguo Su said the global study “further reinforces” the efficacy previously demonstrated in SACHI and provides evidence supporting global registrations of the combination. (AstraZeneca)

The companies said the complete SAFFRON data will be presented at a forthcoming medical meeting and shared with global regulators. The timing and specific jurisdictions for regulatory submissions have not yet been disclosed.

A Significant Milestone for HUTCHMED and AstraZeneca

ORPATHYS is being jointly developed by HUTCHMED and AstraZeneca and commercialized by AstraZeneca. Savolitinib is already approved in China as a treatment for MET exon 14-altered NSCLC, while the combination with TAGRISSO has received approval in China for EGFR-mutated NSCLC with MET amplification following progression on EGFR-targeted therapy. (AstraZeneca)

The SAFFRON success potentially expands the commercial opportunity for savolitinib well beyond China and further validates HUTCHMED’s strategy of developing targeted therapies against molecular mechanisms of resistance.

For AstraZeneca, the results also reinforce TAGRISSO’s position as a central component of treatment across the EGFR-mutated NSCLC disease continuum.

With both PFS and OS significantly improved, the SAFFRON readout represents one of the most important recent developments in targeted therapy for EGFR-mutated lung cancer and sets the stage for potentially broader global use of the savolitinib-TAGRISSO combination.

Top Image: NSCLC, H&E Stain, Wikipedia, by Librepath

References

1. HUTCHMED — SAFFRON Global Phase 3 Readout (Hutch Med)
2. AstraZeneca — Tagrisso plus Orpathys demonstrated statistically significant and clinically meaningful improvements in PFS and OS (AstraZeneca)
3. HUTCHMED — 2025 Interim Report (Hutch Med)
4. HUTCHMED — SAFFRON Phase 3 enrollment announcement (Hutch Med)
5. HUTCHMED — 2026 SACHI and savolitinib portfolio update (Hutch Med)