Osimertinib/Savolitinib Improves Survival in MET-Altered EGFR-Mutant NSCLC

The all-oral combination of osimertinib (Tagrisso) plus savolitinib (Orpathys) significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with platinum/pemetrexed chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non–small cell lung cancer (NSCLC) with MET overexpression, MET amplification, or both whose disease had progressed during osimertinib therapy, according to results from the phase 3 SAFFRON trial (NCT05261399) presented at the 2026 European Society for Medical Oncology (ESMO) Congress and simultaneously published in The New England Journal of Medicine.^1,2

What were the survival outcomes?

The median PFS by blinded independent central review (BICR) was 7.6 months (95% CI, 5.6-9.7) with osimertinib/savolitinib vs 5.4 months (95% CI, 4.2-5.8) with platinum/pemetrexed (HR for disease progression or death, 0.55; 95% CI, 0.42-0.72; P <.001). Osimertinib/savolitinib reduced the risk of disease progression or death by 45% vs platinum-pemetrexed, with a 12-month PFS rate of 36% vs 10%.

In the MET-overexpressed analysis population, the median PFS was 8.5 months (95% CI, 5.7-11.1) vs 5.6 months (95% CI, 4.4-6.7; HR, 0.51; 95% CI, 0.37-0.71; P <.001). In the exploratory MET-amplified analysis population, it was 7.6 months (95% CI, 5.6-9.7) vs 4.2 months (95% CI, 3.1-5.5; HR, 0.48; 95% CI, 0.35-0.66).

The combination also significantly improved OS at the final analysis; the median OS was 17.8 months (95% CI, 15.6-23.7) with osimertinib/savolitinib vs 12.9 months (95% CI, 10.6-16.8) with platinum-pemetrexed (HR for death, 0.68; 95% CI, 0.50-0.91; P = .01), with 12-month OS rates of 70% vs 53%.

“Osimertinib plus savolitinib provided a statistically significant 32% reduction in the risk of death, with a 4.9-month improvement in median OS compared with platinum/pemetrexed,” said presenter Shun Lu, MD, PhD, of the Department of Medical Oncology at Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine in China.

A confirmed objective response by BICR occurred in 51% of the osimertinib/savolitinib group vs 27% of the platinum/pemetrexed group (odds ratio, 2.90; 95% CI, 1.85-4.61).

What was the safety profile?

Grade 3 or higher adverse events (AEs) occurring during treatment were reported in 64% of patients in the osimertinib/savolitinib group and 63% in the platinum/pemetrexed group, and grade 3 or higher treatment-related AEs occurred in 40% vs 52%, respectively. The most frequently reported AEs with osimertinib/savolitinib were peripheral edema (49%), anemia (26%), and diarrhea (26%), which were mostly low grade, whereas the most common AEs with platinum/pemetrexed were anemia (54%), nausea (37%), and decreased platelet counts (31%).

AEs led to treatment discontinuation in 14% vs 8% of patients. AEs that occurred during treatment and led to death were reported in 12 patients (7%) in the osimertinib/savolitinib group and no patients in the platinum/pemetrexed group; 9 of the 12 had documented disease progression before death or NSCLC cited as a cause, and treatment exposure was approximately twice as long in the combination group. Only 1 fatal event was considered treatment related (pneumonitis).

What is the clinical context and trial design?

MET amplification and MET overexpression are together the most common alterations after disease progression during osimertinib in EGFR-mutated advanced NSCLC, reported in approximately 34% of patients in the SAVANNAH trial (NCT03778229), and are associated with poor outcomes and limited targeted options. SAFFRON is an international, open-label, phase 3 trial that screened 1746 patients and randomly assigned 338 patients 1:1 with EGFR-mutated advanced NSCLC and MET overexpression (immunohistochemistry 3+ in at least 90% of tumor cells) and/or amplification (at least 10 gene copies on fluorescence in situ hybridization), determined by central tissue testing, after progression on first- or second-line osimertinib.

Patients received osimertinib at 80 mg once daily plus savolitinib at 300 mg twice daily (n = 171) or intravenous platinum/pemetrexed for 4 cycles followed by pemetrexed maintenance (n = 167). Patients with asymptomatic, stable brain metastases were allowed, and crossover was not permitted.

The primary end point was PFS by BICR. Secondary end points included PFS in the MET-overexpressed population, OS, and safety, tested in a prespecified hierarchy.

What are the implications?

Osimertinib/savolitinib builds on the phase 2 SAVANNAH study and the China-based phase 3 SACHI trial (NCT05015608), and SAFFRON is the first global phase 3 trial of the combination in this setting.

“SAFFRON is the first global phase 3 study showing statistically significant and clinically meaningful improvement in PFS and OS with [osimertinib plus savolitinib] vs platinum/pemetrexed after progression on osimertinib in EGFR-mutant, MET overexpression and/or amplification advanced [NSCLC],” Lu said. “[The] SAFFRON study established the clinical value of an all-oral, biomarker-directed treatment approach targeting both EGFR and MET following progression on osimertinib, reinforcing osimertinib as the backbone treatment across lines of therapy.”

He concluded that osimertinib plus savolitinib “established a new global standard of care” for this MET-selected population. The investigators emphasized that the findings highlight the need for routine tissue rebiopsy and MET testing at progression to identify patients who may benefit from biomarker-directed treatment.

References

1. Lu S, Girard N, Okuma Y, et al. Osimertinib plus savolitinib vs platinum-pemetrexed in patients with EGFR-mutant advanced non-small cell lung cancer with MET overexpression and/or amplification after progression on osimertinib: primary results of the phase 3 SAFFRON study. Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA6.
2. Lu S, Girard N, Yang JC, et al. Osimertinib-savolitinib in advanced NSCLC after progression during EGFR-TKI therapy. N Engl J Med. Published online October 25, 2026. doi:10.1056/NEJMoa2611335