New Drug Application Filed for Savolitinib/Osimertinib in MET+ NSCLC

AstraZeneca has submitted a new drug application (NDA) to the FDA for savolitinib (Orpathys) plus osimertinib (Tagrisso) for patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) whose tumors have MET overexpression or amplification and who experienced disease progression on or after treatment with an EGFR tyrosine kinase inhibitor (TKI), HUTCHMED announced in a news release.¹

The application is supported by the global phase 3 SAFFRON trial (NCT05261399), in which the combination demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) vs doublet platinum-based chemotherapy among patients who progressed on osimertinib.^1 The safety profile was consistent with the known profiles of each medicine, and no new safety concerns were identified. The release did not report specific efficacy figures, and it did not state whether the FDA has accepted the application or set a target action date. The SAFFRON results will be presented in a Presidential Symposium at the upcoming European Society for Medical Oncology (ESMO) Congress 2026.

Unmet Need in MET-Driven Resistance

Third-generation EGFR TKIs have significantly improved outcomes for patients with EGFR-mutated NSCLC, but MET overexpression or amplification is among the most common mechanisms of resistance to these agents.^1 MET-driven progression is associated with poor prognosis, and HUTCHMED noted a significant unmet need for effective and well-tolerated treatment options in this setting. The company estimated that 34% of tumors will develop high levels of MET overexpression or amplification after progression on a third-generation EGFR TKI.

"This filing is an important step toward potentially bringing [savolitinib] plus [osimertinib] to patients in the US, after its approval in China based on the SACHI [phase 3] trial. The success of the global SAFFRON [phase 3] trial reflects the long-standing collaboration between HUTCHMED and AstraZeneca in addressing MET-driven progression in EGFR-mutated lung cancer,” said Johnny Cheng, acting chief executive officer and chief financial officer of HUTCHMED, in a news release.

SAFFRON Study Design

SAFFRON is a randomized, open-label, multicenter, global phase 3 trial evaluating savolitinib at 300 mg twice daily added to osimertinib at 80 mg once daily vs doublet platinum-based chemotherapy.^1,2 The study enrolled 338 patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease progressed following first- or second-line osimertinib. Patients were enrolled at 230 centers across 29 countries in North America, Europe, South America, and Asia.¹

The primary end point is PFS, and a key secondary end point is OS.^1 Patients were prospectively selected using the high MET cutoffs identified in the phase 2 SAVANNAH trial (NCT03778229), in which MET overexpression and amplification were determined by immunohistochemistry and fluorescence in situ hybridization.^1,3

Regulatory and Development Context

For context, the savolitinib/osimertinib combination is approved in China for patients with locally advanced or metastatic EGFR mutation–positive nonsquamous NSCLC with MET amplification after disease progression on EGFR TKI therapy, based on the phase 3 SACHI trial (NCT05015608).^1,4 The combination also received temporary authorization in Switzerland for patients with locally advanced or metastatic EGFR-mutated NSCLC with MET overexpression or amplification who progressed on prior osimertinib, based on results from SAVANNAH.¹

Savolitinib is an oral, highly selective MET TKI that blocks atypical activation of the MET receptor tyrosine kinase pathway caused by mutations such as MET exon 14 skipping alterations, gene amplification, or protein overexpression. As a single agent, it is approved in China for adult patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alterations, and it has conditional approval there for gastric or gastroesophageal junction adenocarcinoma with MET amplification after at least 2 prior systemic therapies. Savolitinib is jointly developed by AstraZeneca and HUTCHMED and commercialized by AstraZeneca.

Osimertinib, a third-generation, irreversible EGFR TKI, is approved as monotherapy in more than 120 countries, including the US, for indications that include first-line treatment of locally advanced or metastatic EGFR-mutated NSCLC, and in combination with chemotherapy in more than 80 countries for the same first-line setting.

REFERENCES

1. HUTCHMED announces submission of US NDA for ORPATHYS plus TAGRISSO in MET-driven EGFR-mutated lung cancer. News release. HUTCHMED. September 29, 2026. Accessed September 29, 2026. https://www.hutch-med.com/orpathys-tagrisso-us-nda-submission/

2. A phase III, randomised, open-label study of savolitinib in combination with osimertinib versus platinum-based doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic non-small cell lung cancer who have progressed on treatment with osimertinib (SAFFRON). ClinicalTrials.gov. Accessed September 29, 2026. https://clinicaltrials.gov/study/NCT05261399

2. A phase II study assessing the efficacy of osimertinib in combination with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic non small cell lung cancer who have progressed following treatment with osimertinib (SAVANNAH). ClinicalTrials.gov. Accessed September 29, 2026. https://clinicaltrials.gov/study/NCT03778229

4. Clinical study to evaluate the efficacy, safety and tolerability of savolitinib + osimertinib versus pemetrexed + platinum in treatment of patients with NSCLC with MET amplification (SACHI). ClinicalTrials.gov. Accessed September 29, 2026. https://clinicaltrials.gov/study/NCT05015608