Savolitinib plus osimertinib has entered regulatory review in Europe and Japan, following a US submission in September 2026. HUTCHMED announced the development on November 2, 2026, with the applications supported by positive results from the global phase III SAFFRON trial, presented at the ESMO Congress 2026 Presidential Symposium and simultaneously published in The New England Journal of Medicine.
In Europe, the European Medicines Agency has validated and accepted AstraZeneca’s application for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with MET overexpression or amplification whose disease progressed on or after EGFR tyrosine kinase inhibitor therapy.
Japan’s Ministry of Health, Labour and Welfare has also accepted an application for the combination, seeking approval for patients with unresectable, advanced or recurrent NSCLC with MET overexpression or amplification following progression on EGFR-targeted therapy.
The combination targets a recognized mechanism of treatment resistance: MET overexpression or amplification, which can develop after treatment with third-generation EGFR tyrosine kinase inhibitors. In SAFFRON, savolitinib plus osimertinib reduced the risk of disease progression or death by 45% and extended median overall survival by 4.9 months compared with chemotherapy.
The European application covers locally advanced or metastatic NSCLC with MET overexpression or amplification after progression on or after EGFR tyrosine kinase inhibitor therapy. Japan’s application seeks approval for unresectable, advanced or recurrent disease following EGFR-targeted treatment.
Inside SAFFRON: Evaluating Dual MET and EGFR Inhibition
SAFFRON is a randomized, open-label, multicenter, global phase III trial evaluating savolitinib at 300 mg twice daily combined with osimertinib at 80 mg once daily versus platinum-based doublet chemotherapy. The study enrolled 338 patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease had progressed following first- or second-line osimertinib.
Patients were enrolled at 230 centers across 29 countries in North America, Europe, South America and Asia. Progression-free survival is the primary endpoint, and overall survival is a key secondary endpoint.
Patients were randomized equally between the two treatment groups: 171 received savolitinib plus osimertinib, and 167 received platinum-pemetrexed chemotherapy. The chemotherapy regimen comprised pemetrexed with either carboplatin or cisplatin every three weeks for four cycles, followed by maintenance pemetrexed. Randomization was stratified by race, baseline brain metastases, and treatment line.
Eligibility required an ECOG performance status of 0-1, and patients with stable central nervous system metastases were permitted. MET status was confirmed through tumor tissue testing after progression. High MET expression required IHC 3+ staining in at least 90% of tumor cells, while amplification required at least 10 MET gene copies by FISH. Patients could qualify through either criterion.
The primary endpoint was progression-free survival assessed by blinded independent central review according to RECIST version 1.1. Additional assessments included investigator-assessed progression-free survival, overall survival, objective response rate, duration of response, disease control and safety.
Patients were prospectively selected using the high MET level cutoffs identified in the phase II SAVANNAH trial. In SAVANNAH, MET overexpression or amplification was assessed using two tests: immunohistochemistry (IHC), which detects specific proteins or markers on the surface of cancer cells, and fluorescence in situ hybridization (FISH), which detects specific DNA sequences in cancer cells.
Check out the latest update about SAFFRON trial presented at ESMO 2026.
Savolitinib: Mechanism of Action and Regulatory Milestones
Savolitinib is a potent, highly selective oral MET tyrosine kinase inhibitor (TKI) that has demonstrated clinical activity in advanced solid tumors. It blocks abnormal activation of the MET receptor tyrosine kinase pathway caused by mutations, including exon 14 skipping alterations and other point mutations, gene amplification or protein overexpression.
Savolitinib was the first selective MET inhibitor approved in China. Its approval covers adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a MET exon 14 skipping alteration. It has also received conditional approval in China for adults with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with MET amplification after failure of at least two previous systemic treatments.
In August 2026, the global, randomized phase III SAFFRON trial reported positive high-level results in the same treatment setting. Compared with platinum-based doublet chemotherapy, savolitinib plus osimertinib demonstrated statistically significant and clinically meaningful improvements in progression-free survival and overall survival.
Osimertinib: EGFR Inhibition and Approved Indications
Osimertinib is a third-generation, irreversible EGFR-TKI with established clinical activity in NSCLC, including the treatment of central nervous system metastases.
Osimertinib is approved as monotherapy in more than 120 countries, including the United States, European Union, China and Japan. Its approved indications include first-line treatment of locally advanced or metastatic EGFR-mutated NSCLC; locally advanced or metastatic EGFR T790M mutation-positive NSCLC; adjuvant treatment of early-stage EGFR-mutated NSCLC; and locally advanced, unresectable NSCLC following platinum-based chemoradiation therapy.
Osimertinib is also approved with chemotherapy in more than 80 countries, including the United States, European Union, China and Japan, for first-line treatment of locally advanced or metastatic EGFR-mutated NSCLC.
NSCLC burden and EGFR mutation prevalence
Non-small cell lung cancer (NSCLC) represents 80-85% of lung cancer diagnoses, and approximately 75% of patients with NSCLC are diagnosed with advanced disease. EGFR mutations are present in around 10-15% of patients with NSCLC in the United States and Europe and 30-40% in Asia.
MET is a receptor tyrosine kinase that plays an essential role in normal cell development. Following disease progression on a third-generation EGFR tyrosine kinase inhibitor, approximately one in three patients’ tumors develop high levels of MET overexpression or amplification, described in the release using the thresholds IHC3+ >90% and FISH10+.
The European and Japanese applications follow the US submission in September 2026, with all three filings supported by the phase III SAFFRON results. In patients whose disease progressed on osimertinib, savolitinib plus osimertinib reduced the risk of progression or death by 45% and the risk of death by 32% compared with platinum-based doublet chemotherapy. Median overall survival reached 17.8 months versus 12.9 months, with no new safety concerns reported.
You can also read: HUTCHMED and AstraZeneca Seek FDA Approval for Savolitinib Plus Osimertinib in MET-Driven EGFR-Mutated Lung Cancer.
