AstraZeneca has announced positive high-level results from the Phase III SAFFRON trial, showing that Tagrisso (osimertinib) plus Orpathys (savolitinib) achieved statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) compared with doublet platinum-based chemotherapy in patients with EGFR-mutated non-small cell lung cancer (NSCLC).
The trial included patients with locally advanced or metastatic EGFR-mutated NSCLC whose tumors had high levels of MET overexpression or amplification and whose disease had progressed following prior treatment with Tagrisso. According to AstraZeneca, SAFFRON is the first global Phase III trial to demonstrate significant improvements in PFS and OS in this setting.
Detailed efficacy results, including hazard ratios and median PFS and OS, have not yet been reported. AstraZeneca said the findings will be presented at a forthcoming medical meeting and shared with regulatory authorities worldwide.
The safety profile of the Tagrisso-Orpathys combination was consistent with the established profiles of the individual medicines, with no new safety findings reported.
Shun Lu, MD, Director of the Shanghai Lung Cancer Center at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, and principal investigator of SAFFRON, said:
“These exciting results from SAFFRON represent a critical advance for patients with EGFR-mutated non-small cell lung cancer experiencing MET-driven resistance after osimertinib, a population with poor outcomes and no biomarker-directed treatment options available that are oral and well-tolerated.”
He highlighted the potential of the combination in patients with MET-driven resistance after osimertinib and emphasized the importance of MET testing to guide treatment decisions.
Susan Galbraith, Executive Vice President, Oncology Haematology R&D at AstraZeneca, highlighted “the clear benefit of adding Orpathys to backbone therapy Tagrisso.” She said the strategy is designed to target MET overexpression or amplification while maintaining suppression of the EGFR pathway, to provide a biomarker-directed, all-oral treatment option for patients in this setting.
Weiguo Su, Chief Executive Officer and Chief Scientific Officer of HUTCHMED, described MET-driven resistance following EGFR-TKI therapy as “a long-standing challenge in clinical practice.” He noted that the SAFFRON findings reinforce efficacy previously demonstrated in the Phase III SACHI trial and could support global regulatory submissions for the combination.
About the SAFFRON Trial
SAFFRON (NCT05261399) is a randomized, open-label, multicenter, global Phase III trial evaluating savolitinib plus osimertinib versus platinum-based doublet chemotherapy in patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression or amplification following disease progression on first- or second-line osimertinib.
Patients in the experimental arm received Orpathys 300 mg twice daily plus Tagrisso 80 mg once daily. The chemotherapy arm received pemetrexed with either cisplatin or carboplatin, followed by pemetrexed maintenance according to the study protocol.
The primary endpoint is PFS, while key secondary endpoints include OS and objective response rate (ORR). AstraZeneca reported that the trial was conducted at approximately 230 centers across 29 countries in North America, Europe, South America, and Asia.
Patients were prospectively selected using the high-MET cutoffs identified in the Phase II SAVANNAH trial. MET overexpression or amplification was assessed using immunohistochemistry and fluorescence in situ hybridization.
MET represents an important mechanism of acquired resistance to EGFR-targeted therapy. AstraZeneca cited data indicating that approximately 34% of tumors develop high levels of MET overexpression or amplification following progression on a third-generation EGFR-TKI.
Tagrisso and Orpathys
Tagrisso is a third-generation irreversible EGFR tyrosine kinase inhibitor developed by AstraZeneca and is used across multiple stages of EGFR-mutated NSCLC.
Orpathys is an oral, potent, and highly selective MET tyrosine kinase inhibitor. It is jointly developed by AstraZeneca and HUTCHMED and commercialized by AstraZeneca.
The Tagrisso-Orpathys combination is already approved in China for patients with locally advanced or metastatic EGFR-mutated NSCLC with MET amplification following disease progression on EGFR-TKI therapy, based on results from the Phase III SACHI trial.
AstraZeneca said the SAFFRON findings will be presented at a forthcoming medical meeting and submitted to global regulatory authorities.
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