AstraZeneca's Tagrisso plus Orpathys cuts death risk by 32% after Tagrisso resistance

AstraZeneca and HUTCHMED reported on 25 October that adding Orpathys (savolitinib) to Tagrisso (osimertinib) beat platinum doublet chemotherapy on both progression-free and overall survival in EGFR-mutated non-small cell lung cancer that had progressed on Tagrisso and carried high MET levels. The SAFFRON results were presented in the Presidential Symposium at the ESMO Congress 2026 in Madrid and published at the same time in The New England Journal of Medicine ¹.

What the trial found

SAFFRON is a randomised, open-label Phase III trial that enrolled 338 patients at 230 centres in 29 countries across North America, Europe, South America and Asia. Patients had progressed after first- or second-line Tagrisso and were selected prospectively using the high MET cut-offs set in the earlier SAVANNAH Phase II study, measured by immunohistochemistry and FISH. The combination arm had 171 patients and the chemotherapy arm 167 ¹.

On the primary endpoint, the combination cut the risk of progression or death by 45% (hazard ratio 0.55; 95% CI 0.42-0.72; p<0.001). Median progression-free survival by blinded independent central review was 7.6 months against 5.4 months, and an estimated 36% of patients on the combination were progression-free at one year compared with 10% on chemotherapy. AstraZeneca said the benefit held across all prespecified subgroups ¹.

Overall survival, the key secondary endpoint, also reached significance. The risk of death fell by 32% (hazard ratio 0.68; 95% CI 0.50-0.91; p=0.010), and median survival was 17.8 months against 12.9 months, a gain of 4.9 months. At one year, an estimated 70% of patients on the combination were alive compared with 53% on chemotherapy ¹.

Grade 3 or higher adverse events from any cause occurred in 64% of the combination arm and 63% of the chemotherapy arm, and the companies reported no new safety concerns. Patients stayed on the combination for a median of 8.5 months, more than twice the 3.5 months in the chemotherapy arm ¹.

What it means for the market

AstraZeneca has already filed a New Drug Application with the US Food and Drug Administration for the combination in patients with MET overexpression or amplification whose disease progressed on or after EGFR tyrosine kinase inhibitor therapy ¹. The pairing is approved in China in this later-line setting on the basis of the SACHI Phase III trial, and Switzerland granted a temporary authorisation based on SAVANNAH ¹. SAFFRON is the first global Phase III trial to show a survival benefit here, according to the companies, which gives regulators in Europe and elsewhere a dataset that China's approval did not rest on ¹.

The commercial logic for AstraZeneca is that a second oral drug extends the life of its EGFR franchise after resistance sets in. Susan Galbraith, who leads oncology haematology R&D at AstraZeneca, described the aim as becoming "the first biomarker-directed, all-oral treatment option in this setting" ¹. AstraZeneca commercialises Orpathys and develops it jointly with HUTCHMED ¹.

The trial also creates a testing requirement. The company cites estimates that about one in three patients' tumours develop high MET overexpression or amplification after a third-generation EGFR inhibitor ¹. Shun Lu of Shanghai Chest Hospital, the principal investigator, said the results reinforce "the critical need for MET testing to guide patient care" ¹. For health systems, uptake will depend on immunohistochemistry and FISH capacity at progression, not only on drug pricing.

Caveats

The trial was open-label. The 4.9-month survival gain comes against platinum-pemetrexed, not against other targeted options, and the data cut-off was 6 July 2026. Results for the MET-amplified subgroup were not formally tested statistically ¹. A second Phase III study, SANOVO, tests the combination in untreated patients but enrolled only in China ¹. The next decision point is the FDA's review of the submitted application.