HUTCHMED savolitinib combo cuts death risk 32% in Phase III NSCLC trial

SAFFRON Phase III data, published in NEJM, show savolitinib plus osimertinib extended median OS by nearly five months over chemotherapy in MET-driven EGFR-mutated

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HUTCHMED has reported the full primary results of its SAFFRON Phase III trial, showing that savolitinib (ORPATHYS) combined with osimertinib (TAGRISSO) significantly extended both progression-free and overall survival versus doublet platinum-based chemotherapy in patients with EGFR-mutated, MET-driven non-small cell lung cancer who had previously progressed on osimertinib. The data were presented at the ESMO Presidential Symposium in Madrid on 25 October and simultaneously published in the New England Journal of Medicine.

The trial enrolled 338 patients across 230 centres in 29 countries. On the primary endpoint, the combination reduced the risk of disease progression or death by 45% compared with chemotherapy (PFS hazard ratio 0.55; 95% CI 0.42–0.72; p<0.001). Median PFS assessed by blinded independent central review was 7.6 months in the combination arm versus 5.4 months in the comparator arm. At 12 months, 36% of patients receiving savolitinib plus osimertinib remained progression-free, against 10% in the chemotherapy group.

Overall survival and safety

On the key secondary endpoint of overall survival, the combination reduced the risk of death by 32% (OS HR 0.68; 95% CI 0.50–0.91; p=0.010), with median OS of 17.8 months versus 12.9 months, a difference of 4.9 months. One-year survival rates were 70% in the combination arm and 53% in the chemotherapy arm. The PFS benefit was consistent across both MET-overexpressed and MET-amplified subgroups, lending confidence to the biomarker-selection strategy prospectively defined in the earlier SAVANNAH Phase II programme.

The safety profile was described as manageable and consistent with the known profiles of each agent. Grade 3 or higher treatment-emergent adverse events occurred in 64% of patients on the combination and 63% on chemotherapy, a near-identical rate despite the combination arm having more than twice the median treatment exposure (8.5 months versus 3.5 months).

Professor Shun Lu, global principal investigator and director of Shanghai Lung Cancer Center, said the results "have the potential to establish a new global standard of care for the third of patients with EGFR-mutated non-small cell lung cancer experiencing MET-driven resistance after osimertinib," emphasising the critical role of MET biomarker testing in guiding patient selection.

Regulatory path and competitive landscape

HUTCHMED and AstraZeneca have already submitted a New Drug Application to the US FDA based on the SAFFRON data. Submissions to the European Medicines Agency and Japan's PMDA are also progressing. The combination carries existing approval in China for MET-amplified EGFRm NSCLC following prior EGFR TKI therapy, based on the earlier SACHI Phase III trial, and a temporary authorisation in Switzerland based on SAVANNAH Phase II results.

SAFFRON is positioned by its investigators as the first global Phase III trial to demonstrate statistically significant PFS and OS benefit in MET-driven osimertinib-resistant NSCLC, a setting where there are currently no approved oral, biomarker-directed options outside China. The indication sits at a competitive intersection: several other MET-directed strategies are in mid-stage development, and amivantamab, the EGFR-MET bispecific antibody from Johnson and Johnson, is approved for distinct EGFR-mutated NSCLC indications and could broaden into overlapping patient populations. The all-oral, biomarker-directed nature of the savolitinib-osimertinib combination is a differentiating commercial argument, particularly in health systems where infusion-based regimens face access or capacity constraints.

Near-term attention will focus on the FDA review timeline, the readout from the companion SANOVO Phase III trial in treatment-naive patients also presented at ESMO, and whether payers accept MET testing as a routine reflex test at progression, a prerequisite for the biomarker-selection model to function at scale.

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