HUTCHMED’s SAFFRON Phase III trial shows savolitinib plus osimertinib reduced the risk of death by 32% in EGFR-mutated NSCLC after osimertinib progression
Written By: Neha Vishwakarma, PharmD
Reviewed By: Pharmacally Editorial Team
HUTCHMED announced on October 25, 2026, that its global Phase III SAFFRON trial met both its primary endpoint of progression-free survival (PFS) and key secondary endpoint of overall survival (OS). Adding ORPATHYS® (savolitinib) to TAGRISSO® (osimertinib) reduced the risk of disease progression or death by 45% and the risk of death by 32% compared with platinum-based chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) and high MET overexpression or amplification following osimertinib treatment.
Presented at the Presidential Symposium of the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, the results were published simultaneously in The New England Journal of Medicine (NEJM).
Targeting MET-driven resistance after osimertinib
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat EGFR-mutated NSCLC. However, acquired resistance frequently limits its long-term effectiveness. MET overexpression or amplification represents an important resistance mechanism in this setting.
SAFFRON (NCT05261399) evaluated whether simultaneously inhibiting EGFR and MET could improve outcomes after osimertinib progression. The trial enrolled 338 patients across 230 centres in 29 countries. Patients were randomized to receive savolitinib 300 mg twice daily plus osimertinib 80 mg once daily, or doublet platinum-based chemotherapy.
Eligibility required high MET expression, defined as immunohistochemistry (IHC) staining of 3+ in at least 90% of tumour cells, MET amplification, defined as at least 10 gene copies by fluorescence in situ hybridization (FISH), or both.
SAFFRON demonstrates improvements in PFS and OS
At the July 6, 2026, data cut-off, the combination demonstrated a statistically significant PFS benefit, assessed by blinded independent central review.
Median PFS was 7.6 months with savolitinib plus osimertinib, compared with 5.4 months with chemotherapy (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.42–0.72; p<0.001). The 12-month PFS rate was 36% versus 10%, respectively.
The OS findings provide an important additional signal. Median OS reached 17.8 months with the combination, compared with 12.9 months with chemotherapy, a difference of 4.9 months (HR, 0.68; 95% CI, 0.50–0.91; p=0.010). At 12 months, 70% of patients receiving the combination were alive, compared with 53% in the chemotherapy arm.
The OS result strengthens the clinical relevance of the PFS improvement. However, the hazard ratio represents a relative reduction in the rate of death over follow-up, not an equivalent reduction in an individual’s absolute probability of dying.
Biomarker findings support patient selection
HUTCHMED reported consistent PFS findings across the MET-overexpressed and MET-amplified analysis sets.
Among patients in the MET-overexpressed set, median PFS was 8.5 months with the combination versus 5.6 months with chemotherapy (HR, 0.51; 95% CI, 0.37–0.71; p<0.001). The 12-month PFS rates were 40% and 11%, respectively.
In the MET-amplified set, median PFS was 7.64 months versus 4.2 months (HR, 0.487; 95% CI, 0.35–0.66). The corresponding 12-month rates were 33% and 8%. No formal statistical testing was conducted for this analysis, so the findings should be interpreted descriptively rather than as independent confirmation of efficacy.
Safety findings require context
Grade 3 or higher treatment-emergent adverse events occurred in 64% of patients receiving savolitinib plus osimertinib and 63% receiving chemotherapy. HUTCHMED reported no new safety concerns and described the combination’s safety profile as manageable.
Median treatment exposure was 8.5 months with the combination, compared with 3.5 months with chemotherapy. Although the similar adverse-event rates are encouraging, longer treatment exposure complicates direct safety comparisons. Detailed event-specific rates, treatment discontinuations and quality-of-life outcomes are important for a fuller assessment of tolerability.
Regulatory implications and remaining questions
AstraZeneca has submitted a US New Drug Application for the combination based on SAFFRON. HUTCHMED also reported that regulatory submissions in Europe and Japan were progressing. US approval remains subject to regulatory review.
The combination is already approved in China for a related post-EGFR TKI setting involving EGFR-mutated, MET-amplified non-squamous NSCLC, based on the Phase III SACHI trial. Separately, the Phase III SANOVO trial evaluated the combination in previously untreated Chinese patients with EGFR-mutated NSCLC and MET overexpression, addressing a different treatment setting.
SAFFRON establishes a significant survival benefit against platinum-based chemotherapy in a biomarker-selected population. Nevertheless, comparisons with newer targeted or antibody-based treatments remain unresolved. Further assessment of subsequent therapies, intracranial outcomes, quality of life and longer-term survival will help define the combination’s broader clinical role.
The findings support MET testing as a potentially important component of treatment selection after osimertinib progression. Their eventual impact will depend on regulatory decisions, access to reliable biomarker testing and confirmation of the benefit-risk profile in clinical practice.
Reference
HUTCHMED Highlights SAFFRON Global Phase III Data Presented at ESMO Congress 2026 and Simultaneously Published in The New England Journal of Medicine, HUTCHMED, 26 October 2026
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 ID NCT05261399
Lu S. et al, Osimertinib-Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy. N Engl J Med. 2026 Oct 25, Epub ahead of print. PMID: 42929693, https://doi.org/10.1056/nejmoa2611335
About the Writer
Neha Vishwakarma (LinkedIn) is a Pharm.D professional with experience in clinical pharmacy, pharmacovigilance, and clinical research. She has hands-on experience in ADR assessment, ICSR processing, medication safety, and clinical data evaluation. Her research background in surgical site infections and antibiotic use supports her focus on evidence-based healthcare writing.