SAFFRON Phase III: Tagrisso Plus Orpathys Improves Progression-Free and Overall Survival in MET-Driven EGFR-Mutated Lung Cancer After Tagrisso

A 338-patient trial against chemotherapy

SAFFRON enrolled patients with locally advanced or metastatic EGFR-mutated NSCLC whose disease had progressed on Tagrisso given in the first or second line, and randomized them to the all-oral pair or to a platinum doublet. AstraZeneca's release calls it the first global Phase III to show significant PFS and OS benefit in this setting and says the safety profile matched the known profiles of each drug, with no new findings. The numbers behind "statistically significant and clinically meaningful" stay unpublished for now. Both companies said the data "will be presented at a forthcoming medical meeting and shared with global regulatory authorities."

Professor Shun Lu, director of the Shanghai Lung Cancer Center at Shanghai Chest Hospital and the trial's principal investigator, framed the result around testing: "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." Susan Galbraith, AstraZeneca's executive vice president for oncology hematology R&D, said the companies "aim to deliver the first biomarker-directed, all-oral option in this setting to patients across the globe."

How MET-driven was defined

The release says patients were prospectively selected "using the high MET level cut-offs identified in the SAVANNAH Phase II trial," where MET status came from two tests, IHC and FISH. The published SAVANNAH paper in Annals of Oncology spells those cut-offs out. The study began at IHC 3+ in at least 50% of tumor cells and/or FISH 5+, meaning five or more MET gene copies or a MET-to-CEP7 ratio of at least 2, then raised the bar after a preliminary analysis to IHC 3+ in at least 90% of cells and/or FISH 10+. In SAVANNAH's 80-patient primary efficacy population at those higher thresholds, savolitinib 300 mg twice daily plus osimertinib produced a confirmed objective response rate of 56.3% and a median PFS of 7.4 months, with peripheral edema (46.0%), nausea (40.5%) and diarrhea (23.2%) the most common adverse events.

Neither company's release names the IHC antibody clone, the FISH probe, the specimen requirement or whether a companion diagnostic is being developed alongside the regulatory filings. AstraZeneca cites an estimate that 34% of tumors develop high MET overexpression or amplification after progression on a third-generation EGFR TKI, the figure that sets the size of the testable population.

China approved the pair, Switzerland authorized it temporarily

In China the pair is approved for EGFR-mutated non-squamous NSCLC with MET amplification after EGFR-TKI progression, on the strength of the SACHI Phase III. Switzerland granted a temporary authorization on the SAVANNAH data for patients with high MET overexpression or amplification after Tagrisso. Orpathys alone is approved in China for MET exon 14 skipping NSCLC and holds a conditional Chinese approval in MET-amplified gastric and gastroesophageal junction adenocarcinoma after two prior lines. AstraZeneca commercializes the drug under a joint development agreement with HUTCHMED, whose chief executive Weiguo Su said the global readout "further reinforces the robust efficacy previously demonstrated in the SACHI Phase III trial" and provides "clear evidence to support global registrations." HUTCHMED's version of the release notes that Su is currently on a leave of absence.

Why This Matters to the APO|APE Reader

On the wording of the two releases, the Chinese SACHI label reads "MET amplification" while SAFFRON enrolled on "MET overexpression or amplification," so a patient whose tumor is IHC 3+ across 90% of cells but FISH-negative qualified for the global trial and would not qualify under the existing Chinese indication. Which definition ends up in any future FDA or EMA label will decide whether a pathology department can answer with an IHC stain or needs FISH as well, and how much post-osimertinib rebiopsy material each answer takes. SAVANNAH's primary efficacy population was 80 of 365 treated patients, a subset defined by dose, prior line and the higher MET threshold, which gives some sense of how many samples can pass through a laboratory for each patient who ends up on the regimen.