EU, Japanese Approval Is Sought for Savolitinib Plus Osimertinib in MET-Driven EGFR-Mutated NSCLC

The European Medicines Agency has validated and accepted a marketing authorization application seeking the approval of savolitinib (Orpathys) plus osimertinib (Tagrisso) for the treatment of patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with MET overexpression or amplification whose disease progressed on or after an EGFR TKI.¹

In Japan, the Ministry of Health, Labour and Welfare accepted for review a new drug application (NDA) seeking approval for the combination in patients with unresectable, advanced or recurrent NSCLC with MET overexpression or amplification following progression on an EGFR TKI. These filings followed the September 2026 submission of a new drug application seeking FDA approval for the regimen.²

The global filings are supported by data from the phase 3 SAFFRON trial (NCT05261399), which were presented in a Presidential Symposium at the 2026 ESMO Congress and published in the New England Journal of Medicine.^1,3 In SAFFRON, savolitinib plus osimertinib (n = 171) significantly improved progression-free survival (PFS) by blinded independent central review vs platinum-based chemotherapy with pemetrexed (Alimta; n = 167) in patients whose disease progressed on osimertinib, with a median PFS of 7.6 months vs 5.4 months, respectively (HR, 0.55; 95% CI, 0.42-0.72; P < .001).^1,3 The combination also improved overall survival (OS), with a median OS of 17.8 months vs 12.9 months (HR, 0.68; 95% CI, 0.50-0.91; P = .010). The 12-month PFS rates were 36% vs 10%, and the 12-month OS rates were 70% vs 53%.

What is the mechanism of action of savolitinib? How was SAFFRON designed?

Savolitinib is an oral, selective MET TKI, and osimertinib is a third-generation, irreversible EGFR TKI.¹ MET overexpression or amplification is a common mechanism of resistance to third-generation EGFR TKIs.

The biomarker cutoffs used in SAFFRON were defined in the phase 2 SAVANNAH trial (NCT03778229), in which analyses identified MET 3+ staining in at least 90% of tumor cells by immunohistochemistry (IHC) and/or at least 10 MET gene copies by fluorescence in situ hybridization (FISH) as the optimal thresholds for savolitinib plus osimertinib after progression on osimertinib.⁴ In that analysis, the confirmed objective response rate (ORR) was 49% in patients meeting these cutoffs vs 9% in those who did not, and the estimated prevalence of high MET levels by these criteria was 34%.

The international, open-label, randomized phase 3 SAFFRON trial enrolled patients with EGFR-mutated, locally advanced or metastatic NSCLC whose disease had progressed during first- or second-line osimertinib and whose tumors had MET overexpression (IHC 3+ in ≥90% of tumor cells), MET amplification (≥10 gene copies on FISH), or both.³

Of 1746 patients screened, 338 were randomly assigned 1:1 to receive osimertinib at 80 mg once daily plus savolitinib at 300 mg twice daily or intravenous platinum-pemetrexed. In the control arm, patients received pemetrexed at 500 mg/m² plus carboplatin (area under the curve 5) or cisplatin at 75 mg/m² every 3 weeks for 4 cycles, followed by pemetrexed maintenance at 500 mg/m².

The primary end point was PFS by blinded independent central review; secondary end points included OS and safety.

What is the safety profile of savolitinib plus osimertinib?

Grade 3 or higher adverse effects (AEs) occurred in 64% of patients in the combination arm and 63% of those in the chemotherapy arm.³ The most frequent AEs with savolitinib plus osimertinib were peripheral edema (49%), anemia (26%), and diarrhea (26%). In the safety population (combination, n = 170; chemotherapy, n = 145), grade 3 or higher treatment-related AEs occurred at respective rates of 40% vs 52%, and AEs led to discontinuation of any study treatment in 14% vs 8% of patients, respectively.⁴

Fatal AEs occurred in 12 patients (7%) in the combination arm and in no patients in the chemotherapy arm; 9 of the 12 had documented disease progression before death or had progression cited as the cause of death. One fatal treatment-related AE, pneumonitis, occurred in the combination arm. The safety profile was consistent with the known profiles of each agent, with no new safety concerns identified.¹

References

1. HUTCHMED announces regulatory filings accepted for review for Orpathys plus Tagrisso in MET-driven EGFR-mutated lung cancer in Europe and Japan. News release. HUTCHMED. November 1, 2026. Accessed November 2, 2026. https://www.globenewswire.com/news-release/2026/11/02/3392807/0/en/hutchmed-announces-regulatory-filings-accepted-for-review-for-orpathys-plus-tagrisso-in-met-driven-egfr-mutated-lung-cancer-in-europe-and-japan.html
2. Hutchmed announces submission of US NDA for Orpathys plus Tagrisso in MET-driven EGFR-mutated lung cancer. News release. September 29, 2026. Accessed September 29, 2026. https://www.hutch-med.com/orpathys-tagrisso-us-nda-submission/
3. Lu S, Girard N, Yang JC, et al. Osimertinib-savolitinib in advanced NSCLC after progression during EGFR-TKI therapy. N Engl J Med. Published online October 25, 2026. doi:10.1056/NEJMoa2611335
4. Ahn MJ, de Marinis F, Cho BC, et al. Evaluation of MET detection methods and cutoffs in EGFR-mutated non-small cell lung cancer following disease progression on osimertinib in the phase II SAVANNAH study. Clin Cancer Res. Published online September 17, 2026. doi:10.1158/1078-0432.CCR-26-0604