In EGFR-mutated lung cancer that progressed on Tagrisso and showed MET alterations, the two-drug targeted combination improved both progression-free and overall survival, though it came with more serious side effects.
Background
Osimertinib (Tagrisso, AstraZeneca) is a standard treatment for EGFR-mutated non-small cell lung cancer, but tumors eventually find a way around it. One common escape route runs through MET, a growth-signaling protein. In the earlier SAVANNAH trial, MET amplification or overexpression was found in about 34% of patients whose cancer progressed on osimertinib [3]. Tumors, it turns out, keep a spare key.
Savolitinib (Orpathys) is a MET inhibitor developed jointly by AstraZeneca and HUTCHMED [1][7]. SAFFRON tested whether adding it to osimertinib could beat the usual next step, platinum-based chemotherapy.
What the Study Found
The results were presented on October 25 in the Presidential Symposium at the ESMO Congress 2026 in Madrid (abstract LBA6) and published online the same day in The New England Journal of Medicine [1][2][4].
SAFFRON (NCT05261399) was a randomized, open-label, global phase 3 trial [3][4]. Of 1,746 patients screened, 338 were randomized: 171 to osimertinib 80 mg daily plus savolitinib 300 mg twice daily, and 167 to pemetrexed plus carboplatin or cisplatin [3][4]. All had EGFR-mutated advanced disease that progressed after osimertinib. Their tumors also showed MET overexpression or amplification, confirmed centrally on a new biopsy [4].
Median progression-free survival, the primary endpoint, was 7.6 months with the combination versus 5.4 months with chemotherapy (hazard ratio 0.55; 95% CI, 0.42-0.72; P<.001), assessed by blinded independent review [3][4]. At 12 months, 36% versus 10% of patients were free of progression [3].
Overall survival also improved. Median survival was 17.8 months versus 12.9 months (HR 0.68; 95% CI, 0.50-0.91; P=.010), and 12-month survival was 70% versus 53% [3][4]. The confirmed response rate was 51% versus 27% [3][4]. Presenter and principal investigator Shun Lu, MD, PhD, of Shanghai Chest Hospital said the combination "establishes a new global standard of care" [4].
Safety
Grade 3 or higher adverse events from any cause were similar: 64% with the combination and 63% with chemotherapy [3][4]. Treatment-related grade 3 or higher events were less common with the combination (40% vs 52%) [4]. However, serious adverse events (41% vs 28%) and discontinuations due to side effects (14% vs 8%) were more frequent with the combination [4][5].
Twelve patients (7%) on the combination had fatal adverse events, compared with none on chemotherapy. Investigators judged one of these deaths, from pneumonitis, to be treatment-related, and nine of the 12 patients had documented disease progression [3][4]. Peripheral edema, or swelling, affected 49% of patients on the combination versus 8% on chemotherapy, while anemia was less common (26% vs 54%) [4].
Limitations
The trial was open-label, although progression was judged by blinded independent reviewers [6]. Overall survival data were only 53% mature [4]. The patient selection was narrow: only 35% of patients with evaluable MET results qualified [4]. The analysis of the MET-amplified subgroup was exploratory [3][4]. Most efficacy reports so far come from the conference presentation and trade press. VBN could not independently review the full NEJM paper.
AstraZeneca and HUTCHMED developed savolitinib, and AstraZeneca markets both drugs [1][7].
What Comes Next
AstraZeneca has submitted a new drug application to the FDA for the combination in MET-overexpressed or MET-amplified NSCLC after EGFR-targeted therapy [8]. No FDA decision date has been reported. The combination is already approved in China for a related indication [7]. If approved in the U.S., it would offer a targeted alternative to chemotherapy for a selected group of patients. Identifying those patients requires a new biopsy and MET testing after osimertinib stops working [4].
This article is for informational purposes only. Readers should consult their clinician about any health concerns.
References
HUTCHMED. "HUTCHMED Highlights SAFFRON Global Phase III Data Presented at ESMO Congress 2026 and Simultaneously Published in The New England Journal of Medicine." GlobeNewswire. October 25, 2026. https://globenewswire.com/news-release/2026/10/26/3387782/0/en/hutchmed-highlights-saffron-global-phase-iii-data-presented-at-esmo-congress-2026-and-simultaneously-published-in-the-new-england-journal-of-medicine.html
Lu S, Girard N, Yang JC, et al.; SAFFRON Investigators. "Osimertinib-Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy." New England Journal of Medicine. Published online October 25, 2026. doi:10.1056/NEJMoa2611335. PMID 42929693. https://doi.org/10.1056/NEJMoa2611335
Cancer Network Staff. "Osimertinib/Savolitinib Improves Survival in MET-Altered EGFR-Mutant NSCLC." Cancer Network. October 25, 2026. https://www.cancernetwork.com/view/osimertinib-savolitinib-improves-survival-in-met-altered-egfr-mutant-nsclc
Broderick JM. "ESMO 2026 Presidential Symposium II Showcases OS-Improving LBAs in Lung and GI Cancers." Targeted Oncology. October 25, 2026. https://www.targetedonc.com/view/esmo-2026-savolitinib-presidential-symposium-divarasib-nsclc-krascendo1-saffron-clarity-gastric01-harmoni-gi1
Adamou C. "Targeted Combination Improves Lung Cancer Survival: ESMO 2026." EMJ. October 25, 2026. https://www.emjreviews.com/oncology/news/targeted-combination-improves-lung-cancer-survival-esmo-2026/
Gevorgyan A. "SAFFRON Phase III." OncoDaily. October 25, 2026. https://oncodaily.com/oncolibrary/lung-oncology/saffron-phase-iii
AstraZeneca. "Tagrisso plus Orpathys improved PFS and OS in EGFR-mutated lung cancer" (SAFFRON topline). August 17, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/tagrisso-orpathys-improved-pfs-os-egfrm-lung.html
OncLive Staff. "Savolitinib Plus Osimertinib NDA Submitted to FDA for MET-Driven EGFR-Mutated NSCLC." OncLive. September 29, 2026. https://www.onclive.com/view/savolitinib-plus-osimertinib-nda-submitted-to-fda-for-met-driven-egfr-mutated-nsclc
