November 2nd, 2026
Summary by Catlin Nalley
An all-oral targeted therapy combination of osimertinib and savolitinib significantly improved progression-free (PFS) and overall survival (OS) compared with platinum–pemetrexed chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) whose tumors had MET overexpression and/or amplification and whose disease progressed following osimertinib, according to results from the phase III SAFFRON trial presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid (Abstract LBA6).
The combination reduced the risk of disease progression or death by 45% and the risk of death by 32%. The findings, presented by Shun Lu, MD, PhD, of Shanghai Chest Hospital and Shanghai Jiao Tong University School of Medicine, China, were simultaneously published in The New England Journal of Medicine (2026; doi.org/10.1056/NEJMoa2611335).
Clinical Trial Details
The global, randomized, open-label, phase III SAFFRON (NCT05261399) trial enrolled adults with locally advanced or metastatic EGFR-mutated NSCLC that had progressed following first- or second-line osimertinib. Eligible tumors had MET overexpression, defined as immunohistochemistry (IHC) 3+ staining in at least 90% of tumor cells, and/or MET amplification, defined as at least 10 MET gene copies by fluorescence in situ hybridization (FISH).
Investigators randomized 338 patients to receive either osimertinib plus savolitinib (171 patients) or platinum–pemetrexed chemotherapy (167 patients). The experimental arm received osimertinib 80 mg once daily and savolitinib 300 mg twice daily. The comparator arm received pemetrexed with carboplatin or cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or treatment discontinuation.
The primary endpoint was PFS assessed by blinded independent central review (BICR) using RECIST version 1.1 criteria. Secondary endpoints included OS, investigator-assessed PFS, response outcomes, and safety. The data cutoff was July 6, 2026.
The osimertinib–savolitinib combination significantly improved the primary endpoint. Median PFS by BICR was 7.6 months, compared with 5.4 months for platinum–pemetrexed (HR: 0.55; 95% CI: 0.42–0.72; P<.001). At 12 months, an estimated 36% of patients receiving targeted therapy remained progression-free, compared with 10% in the chemotherapy arm.
The PFS benefit was consistent across prespecified subgroups, including patients with MET overexpression and those with MET amplification. In the MET-overexpressed subgroup, median PFS was 8.5 months with the combination versus 5.6 months with chemotherapy (HR: 0.51). Among patients with MET-amplified tumors, median PFS was 7.6 versus 4.2 months (HR: 0.48). The MET-amplified subgroup analysis was not formally tested for statistical significance.
OS, a key secondary endpoint, also favored the combination. Median OS was 17.8 months with osimertinib–savolitinib versus 12.9 months with chemotherapy, representing a 32% reduction in the risk of death (HR: 0.68; 95% CI: 0.50–0.91; P=.010). At 12 months, estimated OS rates were 70% and 53%, respectively. The OS analysis was 53% mature at the data cutoff.
Response outcomes further supported the combination's activity. The objective response rate was 51% with osimertinib–savolitinib versus 27% with chemotherapy. Median duration of response was 9.7 months compared with 5.7 months, respectively.
Safety Profile & Tolerability
Treatment-emergent adverse events (TEAEs) of any cause occurred in 99% of patients receiving osimertinib–savolitinib and 97% receiving chemotherapy. Grade 3 or higher TEAEs occurred in 64% and 63%, respectively. Serious TEAEs were more frequent with the combination (41% versus 28%), and adverse events led to treatment discontinuation in 14% versus 8%.
However, grade 3 or higher treatment-related adverse events occurred less frequently with osimertinib–savolitinib than with chemotherapy (40% versus 52%). The most common adverse events associated with the combination included peripheral edema, nausea, and increased creatine kinase. Investigators reported no new safety signals, describing the overall safety profile as manageable and consistent with the known effects of the individual agents.
Key Takeaways
SAFFRON is the first global, phase III study demonstrating statistically significant and clinically meaningful improvements in PFS and OS with osimertinib plus savolitinib versus platinum–pemetrexed, after progression on osimertinib, in EGFRm MET-overexpressed and/or -amplified advanced NSCLC, according to Lu and colleagues.
“These results have the potential to establish a new global standard of care for the third of patients with EGFR-mutated non-small cell lung cancer experiencing high levels of MET-driven resistance after osimertinib,” Lu said in a statement accompanying the results.
“There are currently no well-tolerated, oral, biomarker-directed treatment options to address this frequent driver of disease progression,” he noted. “Osimertinib plus savolitinib significantly extended median overall survival by nearly 5 months in this later-line setting, establishing a new clinical benchmark and reinforcing the critical need for MET testing to guide patient care.”
Catlin Nalley is a contributing writer.