The SAFFRON Phase III trial has shown that an oral targeted combination can improve both progression-free and overall survival in patients with EGFR-mutant non-small cell lung cancer (NSCLC) and MET-driven resistance to osimertinib, according to AstraZeneca (LSE/STO/NYSE: AZN). The result could establish a new biomarker-directed treatment option for patients who progress on Tagrisso (osimertinib).
The global trial tested savolitinib (Orpathys), a selective MET tyrosine kinase inhibitor (TKI) co-developed by AstraZeneca and HUTCHMED (China) Limited (Nasdaq/AIM: HCM; HKEX: 13), in combination with osimertinib against platinum-based doublet chemotherapy. SAFFRON enrolled 345 patients with EGFR-mutant locally advanced or metastatic NSCLC with high MET overexpression or amplification whose disease had progressed on first- or second-line osimertinib.
The combination met the primary endpoint of progression-free survival (PFS) and key secondary endpoint of overall survival (OS), producing statistically significant and clinically meaningful improvements over chemotherapy, the companies said. No hazard ratios or median PFS or OS figures were disclosed in the top-line announcement, with full results due at a forthcoming medical meeting. The safety profile was consistent with the established profiles of the two drugs, with no new safety findings reported.
MET amplification and overexpression are important mechanisms of acquired resistance to EGFR TKIs. Savolitinib inhibits aberrant MET signaling while continued osimertinib treatment maintains EGFR suppression, allowing the combination to target both the original oncogenic driver and a major pathway through which tumors can escape EGFR inhibition. AstraZeneca estimates that high-level MET overexpression or amplification occurs in approximately 34% of tumors following progression on third-generation EGFR TKIs.
Osimertinib is already widely approved across EGFR-mutant NSCLC, while the savolitinib-osimertinib combination is approved in China for patients with MET-amplified disease following EGFR-TKI treatment. That approval was supported by the SACHI Phase III trial, which reported median investigator-assessed PFS of 8.2 months with the combination versus 4.5 months with chemotherapy. The combination has also received temporary authorization in Switzerland based on Phase II SAVANNAH data. SAFFRON now provides global Phase III evidence that could support regulatory filings in the US, EU, and other markets.