HUTCHMED advances its ORPATHYS–TAGRISSO combination to regulatory review in Europe and Japan, supported by positive SAFFRON Phase III survival results.
Written By: Siddhi Bhadekar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
HUTCHMED (China) announced on November 1, 2026, that regulatory applications for ORPATHYS® (savolitinib) combined with TAGRISSO® (osimertinib) have been accepted for review in Europe and Japan. Both applications were submitted by AstraZeneca, HUTCHMED’s co-development and commercialization partner, for patients with MET-driven non-small cell lung cancer (NSCLC) whose disease progressed following EGFR tyrosine kinase inhibitor (TKI) treatment.
The regulatory progress follows positive results from the global Phase III SAFFRON trial, which demonstrated improvements in both progression-free survival (PFS) and overall survival (OS) compared with platinum-based chemotherapy.
EMA and MHLW Accept Applications for Review
In Europe, the European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for patients with locally advanced or metastatic NSCLC carrying MET overexpression or amplification following progression on or after EGFR-TKI treatment.
In Japan, the Ministry of Health, Labour and Welfare (MHLW) has accepted a New Drug Application (NDA) for unresectable, advanced or recurrent NSCLC with the same MET characteristics following EGFR-TKI therapy.
These developments follow AstraZeneca’s September 2026 NDA submission to the US Food and Drug Administration (FDA), placing the combination under regulatory consideration in three major markets. The EMA validation and Japanese acceptance indicate that the applications have entered regulatory assessment, not that marketing approval has been granted.
The combination is already approved in China for EGFR mutation-positive non-squamous NSCLC with MET amplification following EGFR-TKI progression, based on the Phase III SACHI trial. It also holds temporary authorization in Switzerland based on the Phase II SAVANNAH study.
Targeting MET-Driven Resistance After Osimertinib
Osimertinib, a third-generation irreversible EGFR-TKI, has improved treatment outcomes in EGFR-mutated NSCLC. However, acquired resistance remains a major challenge. MET overexpression or amplification can activate alternative growth signalling, allowing tumour cells to bypass EGFR inhibition and continue proliferating.
Savolitinib is an oral, selective MET-TKI designed to inhibit this signalling pathway. Combining it with osimertinib aims to suppress both MET-driven resistance and the underlying EGFR signalling pathway.
The clinical rationale is particularly relevant because patients developing MET-mediated resistance after osimertinib have had limited targeted treatment options, with platinum-based chemotherapy commonly used in this setting.
SAFFRON Phase III Trial Demonstrates PFS and OS Benefits
SAFFRON (NCT05261399) was a randomized, open-label, global Phase III trial involving 338 patients with EGFR-mutated, locally advanced or metastatic NSCLC whose disease progressed during osimertinib treatment.
Patients received savolitinib 300 mg twice daily plus osimertinib 80 mg once daily or intravenous platinum-pemetrexed chemotherapy. Eligibility required high MET expression, defined as IHC 3+ staining in at least 90% of tumour cells, MET amplification with at least 10 gene copies by fluorescence in situ hybridization (FISH), or both.
The primary endpoint was PFS assessed by blinded independent central review, while OS was a key secondary endpoint.
The combination met its primary endpoint, reducing the risk of disease progression or death by 45% compared with chemotherapy (HR 0.55; 95% CI 0.42–0.72; p<0.001). Median PFS was 7.6 months versus 5.4 months.
The OS findings also favoured the combination. The risk of death was reduced by 32% (HR 0.68; 95% CI 0.50–0.91; p=0.010), with median OS reaching 17.8 months compared with 12.9 months for chemotherapy, representing a 4.9-month difference.
At 12 months, estimated PFS rates were 36% versus 10%, while OS rates were 70% versus 53%, respectively.
Subgroup findings further supported activity across the biomarker-selected population. Median PFS in patients with MET overexpression was 8.5 months with the combination versus 5.6 months with chemotherapy (HR 0.51). In the MET-amplified subgroup, median PFS was 7.64 versus 4.2 months (HR 0.487). No formal statistical testing was conducted for the latter subgroup.
Safety Profile
The combination produced a safety profile consistent with the known effects of the two medicines. The most frequently reported adverse events included peripheral edema (49%), anemia (26%) and diarrhea (26%). Grade 3 or higher treatment-emergent adverse events occurred in 64% of patients receiving the combination and 63% receiving chemotherapy. Serious adverse events and treatment discontinuations were also more frequent in the combination arm, at 41% versus 28% and 14% versus 8%, respectively.
Clinical Implications
SAFFRON provides clinically relevant evidence that targeting MET-mediated resistance while maintaining EGFR inhibition can improve both PFS and OS compared with chemotherapy following osimertinib progression. The survival benefit strengthens the case for a biomarker-directed, chemotherapy-free oral treatment approach.
However, the additional serious adverse events and treatment discontinuations warrant consideration alongside the efficacy findings. Treatment selection will also depend on reliable identification of MET overexpression or amplification through appropriate diagnostic testing.
With regulatory applications now under review in Europe and Japan, alongside the US FDA submission, the next important milestone will be the independent benefit-risk assessments by regulators. The filings represent meaningful progress for the combination, although approval and its eventual clinical positioning remain subject to regulatory decisions.
References
HUTCHMED Announces Regulatory Filings Accepted for Review for ORPATHYS® plus TAGRISSO® in MET-Driven EGFR-Mutated Lung Cancer in Europe and Japan, HUTCHMED, 02 November 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
About the Writer
Siddhi Rajendra Bhadekar (Linkedin) is an M.Pharm professional with expertise in medical and scientific writing, literature review, publication writing, and evidence synthesis, supported by four peer-reviewed publications.
She brings working knowledge of ICH-GCP, MedDRA, pharmacovigilance, ADR/AE reporting, clinical data management, and regulatory documentation.
With experience across pharmaceutical R&D, Quality Control, and Quality Assurance, she combines scientific research skills with strong attention to accuracy and detail.
Her background in manuscript development, publication planning, and scientific communication enables her to translate complex healthcare information into clear, reliable content.