According to results from the phase III SAFFRON trial, the combination of osimertinib and savolitinib significantly improved progression-free and overall survival compared with platinum-based chemotherapy in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) with MET overexpression, MET amplification, or both following disease progression during osimertinib therapy. The findings were presented at the European Society for Medical Oncology (ESMO) Congress 2026 (Abstract LBA6) and simultaneously published by Lu et al in The New England Journal of Medicine.
Study Details
The international, open-label trial enrolled patients with locally advanced or metastatic NSCLC harboring an EGFR mutation who experienced disease progression during first- or second-line osimertinib therapy. Eligible patients had MET overexpression, defined as immunohistochemical staining intensity of 3+ in ≥ 90% of tumor cells; MET amplification, defined as ≥ 10 MET gene copies on fluorescence in situ hybridization; or both.
Between August 2022 and September 2025, 1,746 patients were screened for eligibility. Of these, 338 were randomly assigned to receive osimertinib at 80 mg once daily plus savolitinib at 300 mg twice daily (n = 171) or platinum plus pemetrexed (n = 167). The chemotherapy regimen consisted of four 21-day cycles of pemetrexed plus cisplatin or carboplatin, followed by pemetrexed maintenance. The primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included overall survival and safety.
The median age was 64 years in both groups, and 31% of patients had brain metastases at baseline. Overall, 72% had MET overexpression, 72% had MET amplification, and 45% had both alterations.
Key Results
Median progression-free survival was 7.6 months with osimertinib plus savolitinib vs 5.4 months with platinum plus pemetrexed (hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.42–0.72; P < .001). Estimated 12-month progression-free survival rates were 36% and 10%, respectively.
Median overall survival was also significantly longer with osimertinib plus savolitinib, at 17.8 months vs 12.9 months with platinum plus pemetrexed (HR = 0.68, 95% CI = 0.50–0.91; P = .01). Estimated 12-month overall survival rates were 70% and 53%, respectively. Confirmed objective responses occurred in 51% vs 27% of patients.
Among patients with MET overexpression, median progression-free survival was 8.5 months with osimertinib plus savolitinib vs 5.6 months with platinum plus pemetrexed (HR = 0.51, 95% CI = 0.37–0.71; P < .001). In the exploratory MET-amplified population, corresponding values were 7.6 and 4.2 months (HR = 0.48, 95% CI = 0.35–0.66).
The most common adverse events with osimertinib plus savolitinib were peripheral edema (49%), anemia (26%), and diarrhea (26%). Grade 3 or higher adverse events occurred in 64% of patients receiving osimertinib plus savolitinib and 63% receiving platinum plus pemetrexed. Serious adverse events occurred in 41% and 28%, respectively, and treatment discontinuation due to adverse events occurred in 14% and 8%. Adverse events leading to death were reported in 7% of patients receiving osimertinib plus savolitinib and none receiving platinum plus pemetrexed.
The authors concluded: “Osimertinib/savolitinib led to significantly longer progression-free and overall survival than platinum/pemetrexed among patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression, MET amplification, or both that had progressed during osimertinib therapy.”
Shun Lu, MD, of the Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China, is the corresponding author for the New England Journal of Medicine article.
DISCLOSURE: The study was supported by AstraZeneca. For full disclosures of the study authors, visit nejm.org.
