Osimertinib (Tagrisso) plus savolitinib (Orpathys) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) vs platinum-based doublet chemotherapy in patients with EGFR-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) with MET overexpression or amplification who progressed on prior osimertinib treatment, according to topline findings from the phase 3 SAFFRON trial (NCT05261399).1,2
The trial marked the first global phase 3 study to show statistically significant PFS and OS benefits in this MET-driven, osimertinib-resistant setting, according to the release.1 Full data are expected to be presented at a forthcoming medical meeting and submitted to global regulatory authorities.
“These exciting results from SAFFRON represent a critical advance for patients with EGFR-mutated NSCLC experiencing MET-driven resistance after osimertinib, a population with poor outcomes and no biomarker-directed treatment options available that are oral and well-tolerated,” lead study investigator Shun Lu, MD, said in a news release.
Lu is director of the Shanghai Lung Cancer Center at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine in China.
SAFFRON Trial in MET-Driven, Osimertinib-Resistant EGFR-Mutated NSCLC: Key Takeaways
- Osimertinib plus savolitinib significantly improved both PFS and OS vs platinum-based chemotherapy in EGFR-mutated NSCLC with MET overexpression or amplification after osimertinib progression.
- The trial enrolled 338 patients across 230 centers in 29 countries, the first global phase 3 study to show significant survival benefits in this resistance setting.
- The safety profile was consistent with the known profiles of osimertinib and savolitinib, with no new safety findings reported.
What was the rationale for the SAFFRON trial?
MET overexpression or amplification is among the most common mechanisms of acquired resistance to third-generation EGFR TKIs such as osimertinib, developing in an estimated 34% of tumors and contributing to progression in approximately one in three patients treated with osimertinib. Patients whose tumors develop MET-driven resistance have historically lacked an oral, biomarker-directed treatment option, with standard care after progression on osimertinib typically consisting of platinum-based chemotherapy.1
Osimertinib remains the standard EGFR-TKI backbone across treatment lines in EGFR-mutated NSCLC. Savolitinib, an oral, potent, and highly selective MET-TKI, is already approved in China in combination with osimertinib for patients with EGFR-mutated locally advanced or metastatic NSCLC with MET amplification following progression on EGFR-TKI therapy, a decision based on data from the phase 3 SACHI trial (NCT05015608).
How was the SAFFRON trial designed?
SAFFRON is a randomized, open-label, multicenter, global phase 3 trial that enrolled 338 patients across 230 centers in 29 countries in North America, Europe, South America, and Asia. Eligible patients had EGFR-mutated locally advanced or metastatic NSCLC with MET overexpression or amplification and had progressed on first- or second-line osimertinib. Patients were randomly assigned to savolitinib at 300 mg twice daily plus osimertinib at 80 mg once daily, or to platinum-based doublet chemotherapy (pemetrexed plus cisplatin or carboplatin, followed by pemetrexed maintenance).1,2 The primary end point was PFS; key secondary end points included OS and objective response rate.
What is the safety profile of osimertinib plus savolitinib?
The safety profile of osimertinib plus savolitinib in SAFFRON was consistent with the known safety profiles of each agent individually, and no new safety findings were reported.1
What are the next steps for osimertinib plus savolitinib in EGFR-mutated NSCLC?
“These data demonstrate the clear benefit of adding [savolitinib] to backbone therapy [osimertinib] to address MET overexpression or amplification while maintaining EGFR suppression,” Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca, said in the news release. “By combining [savolitinib] and [osimertinib], with its established efficacy, safety profile and central nervous system protection, we aim to deliver the first biomarker-directed, all-oral option in this setting to patients across the globe. This further strengthens our leadership in EGFR-mutated lung cancer, reinforcing our strategy to improve patient outcomes across stages and through lines of therapy with novel combinations.”
“Overcoming MET-driven resistance after EGFR-TKI therapy has been a long-standing challenge in clinical practice. The SAFFRON global study further reinforces the robust efficacy previously demonstrated in the SACHI phase 3 trial that supported approval in China, with the results providing clear evidence to support global registrations of the [osimertinib] and [savolitinib] combination,” Weiguo Su, chief executive officer and chief scientific officer of HUTCHMED, added. “We are grateful to everyone who supported this trial. Together with AstraZeneca, we look forward to potentially bringing this landmark treatment to patients around the world.”
References
- Tagrisso plus Orpathys demonstrated statistically significant and clinically meaningful improvements in progression-free and overall survival in MET-driven EGFR-mutated lung cancer after progression on Tagrisso. News release. AstraZeneca. August 17, 2026. Accessed August 17, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/tagrisso-orpathys-improved-pfs-os-egfrm-lung.html
- Savolitinib plus osimertinib versus platinum-based doublet chemotherapy in participants with non-small cell lung cancer who have progressed on osimertinib treatment (SAFFRON). ClinicalTrials.gov. August 8, 2026. Accessed August 17, 2026. https://clinicaltrials.gov/study/NCT05261399
