AstraZeneca Submits US NDA for ORPATHYS Plus TAGRISSO in MET-Driven EGFR-Mutated NSCLC
核心洞察
AstraZeneca has filed a US New Drug Application for ORPATHYS (savolitinib) plus TAGRISSO (osimertinib) in locally advanced or metastatic MET-driven EGFR (搜索)-mutated NSCLC.
The filing is supported by the global SAFFRON Phase III trial, which showed statistically significant and clinically meaningful gains in progression-free and overall survival versus platinum-based chemotherapy.
SAFFRON enrolled 338 patients across 230 centers in 29 countries whose disease progressed on or after TAGRISSO, with MET status selected using SAVANNAH-derived cut-offs.
AstraZeneca has submitted a New Drug Application to the US Food and Drug Administration (搜索) for ORPATHYS (savolitinib) plus TAGRISSO (osimertinib) in patients with locally advanced or metastatic non-small cell lung cancer (搜索) (NSCLC) whose tumors carry MET overexpression or amplification and whose disease progressed on or after an epidermal growth factor receptor (EGFR (搜索)) tyrosine kinase inhibitor (TKI) therapy, HUTCHMED announced on Sept. 28, 2026.
The application seeks approval for a biomarker-directed, all-oral, chemotherapy-free treatment option in a setting where resistance to third-generation EGFR (搜索)-TKIs is common and prognosis is poor.
SAFFRON Phase III Results
The NDA is supported by the global SAFFRON Phase III trial, which HUTCHMED describes as the first global Phase III study to demonstrate statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) in this treatment setting. The combination was compared with doublet platinum-based chemotherapy in patients who had progressed on TAGRISSO.
The safety profile was consistent with the known profiles of each medicine, and no new safety concerns were identified. The results are scheduled for presentation in a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2026.
SAFFRON is a randomized, open-label, multi-center trial that enrolled 338 patients with EGFR (搜索)-mutated, locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease progressed following first- or second-line treatment with TAGRISSO. Patients were enrolled at 230 centers across 29 countries, including North America, Europe, South America and Asia. The primary endpoint is PFS, with OS as a key secondary endpoint.
Patients were prospectively selected using the high MET level cut-offs identified in the SAVANNAH Phase II trial. In SAVANNAH, MET overexpression or amplification levels were determined by two tests: immunohistochemistry (IHC), which detects whether cancer cells carry a particular protein or marker on their surface, and fluorescence in situ hybridization (FISH), which detects a specific DNA sequence from cancer cells.
Dosing and Mechanism
In SAFFRON, ORPATHYS was given at 300 mg twice daily added to TAGRISSO at 80 mg once daily. ORPATHYS is an oral, potent and highly selective MET TKI that blocks atypical activation of the MET receptor tyrosine kinase pathway arising from mutations such as exon 14 skipping alterations or other point mutations, gene amplification or protein overexpression. TAGRISSO is a third-generation, irreversible EGFR (搜索)-TKI with clinical activity in NSCLC, including the treatment of central nervous system metastases.
Resistance and Unmet Need
Third-generation EGFR (搜索)-TKIs have significantly improved outcomes for patients with EGFR-mutated NSCLC, but MET overexpression or amplification is one of the most common mechanisms of resistance to this drug class. MET-driven progression is associated with poor prognosis, and HUTCHMED states there remains a significant unmet need for effective and well-tolerated options in this setting. An estimated 34% of tumors develop high levels of MET overexpression or amplification after progression on a third-generation EGFR TKI.
Lung cancer is the leading cause of cancer death globally, accounting for almost one in four (23%) cancer deaths. Between 80% and 85% of patients are diagnosed with NSCLC, and approximately 75% of NSCLC patients are diagnosed with advanced disease. About 10% to 15% of NSCLC patients in the US and Europe, and 30% to 40% of patients in Asia, have EGFR (搜索)-mutated NSCLC.
Regulatory History of the Combination
ORPATHYS is being jointly developed by AstraZeneca and HUTCHMED and is commercialized by AstraZeneca. In China, ORPATHYS is approved for adult patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alteration, the first selective MET inhibitor approved in the country, and holds conditional approval for locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with MET amplification after at least two prior systemic treatments.
The ORPATHYS plus TAGRISSO combination is approved in China for patients with locally advanced or metastatic EGFR (搜索) mutation-positive non-squamous NSCLC with MET amplification after progression on EGFR TKI therapy, based on the SACHI Phase III trial. It also received temporary authorization in Switzerland for locally advanced or metastatic EGFR-mutated NSCLC with high levels of MET overexpression or amplification after prior TAGRISSO, based on the global SAVANNAH Phase II trial. SAFFRON reported positive high-level results in August 2026.
TAGRISSO is approved as monotherapy in more than 120 countries, including the US, EU, China and Japan, for first-line treatment of locally advanced or metastatic EGFR (搜索)-mutated NSCLC, for locally advanced or metastatic EGFR T790M mutation-positive NSCLC, as adjuvant treatment of early-stage EGFR-mutated NSCLC, and for locally advanced, unresectable NSCLC following platinum-based chemoradiation. It is also approved in combination with chemotherapy in more than 80 countries for first-line treatment of locally advanced or metastatic EGFR-mutated NSCLC.
"This filing is an important step toward potentially bringing ORPATHYS plus TAGRISSO to patients in the US, after its approval in China based on the SACHI Phase III trial," said Johnny Cheng, Acting Chief Executive Officer and Chief Financial Officer of HUTCHMED. "The success of the global SAFFRON Phase III trial reflects the long-standing collaboration between HUTCHMED and AstraZeneca in addressing MET-driven progression in EGFR (搜索)-mutated lung cancer."