Phase 3 trial completed — SAFFRON (NCT05261399), published in NEJM 2026 China — approved for MET-amplified disease U.S. — new drug application filed with the FDA; Japan and EU — filings in progress
A new option for Tagrisso resistance treatment is getting closer. In people with EGFR-mutated lung cancer whose disease progressed on Tagrisso (osimertinib) and whose tumors show MET alterations, taking savolitinib (brand name Orpathys) together with Tagrisso extended median overall survival by 4.9 months compared with chemotherapy. These are the results of the international phase 3 SAFFRON trial, presented at the European Society for Medical Oncology congress (ESMO 2026) on October 25, 2026 and published the same day in the New England Journal of Medicine.
What is new: two oral targeted drugs taken together
Tagrisso is a third-generation targeted drug for non-small cell lung cancer with EGFR mutations and is the standard first-line treatment in many countries. Many patients benefit for a long time, but over time cancer cells can find another route to grow and the drug stops working. This is called resistance.
One of the main causes of resistance is MET, a receptor protein on the cell surface that receives growth signals. When MET becomes overexpressed or its gene copies multiply (amplification), cancer cells can keep receiving growth signals through this MET bypass even while EGFR is blocked. AstraZeneca estimates that about 34% of tumors that progress after a third-generation EGFR inhibitor develop high MET overexpression or amplification.
Savolitinib is an oral drug that blocks MET signaling. In SAFFRON, patients took Tagrisso 80 mg once daily together with savolitinib 300 mg twice daily. The approach blocks the EGFR and MET routes at the same time: Tagrisso is continued and one drug is added. Both are pills, so clinic visits are usually less demanding than with intravenous chemotherapy.
Who is eligible: Tagrisso-resistant lung cancer with confirmed MET alterations
Patients in SAFFRON met all of the following conditions.
- Locally advanced or metastatic non-small cell lung cancer with an EGFR mutation
- Disease progression during first- or second-line Tagrisso
- MET overexpression (immunohistochemistry IHC 3+ in at least 90% of tumor cells) or MET amplification (at least 10 gene copies by FISH) confirmed by central laboratory testing
Patients with stable brain metastases without symptoms could also take part. Of 1,746 people tested, 338 met the criteria. That is why re-checking MET status with a tumor biopsy at the time of Tagrisso resistance is an important step before considering this treatment.
SAFFRON results: median overall survival of 17.8 months
SAFFRON (NCT05261399) is an international randomized phase 3 trial conducted at 230 centers in 29 countries. It compared 171 patients receiving savolitinib plus Tagrisso with 167 patients receiving platinum-based chemotherapy. The chemotherapy group received cisplatin or carboplatin with pemetrexed for four cycles, followed by pemetrexed maintenance.
| Measure | Savolitinib + Tagrisso | Chemotherapy |
|---|---|---|
| Median overall survival | 17.8 months | 12.9 months |
| Hazard ratio for death | 0.68 (95% CI 0.50–0.91) — 32% lower risk of death | |
| 12-month survival rate | 70% | 53% |
| Median progression-free survival | 7.6 months | 5.4 months |
| Hazard ratio for progression | 0.55 (95% CI 0.42–0.72) | |
| 12-month progression-free rate | 36% | 10% |
| Confirmed response rate | 51% | 27% |
| Grade 3 or higher treatment-related adverse events | 40% | 52% |
Sources: HUTCHMED ESMO 2026 release and CancerNetwork summary (2026-10-25). Progression-free survival and response rate were assessed by blinded independent central review. Response rate is the share of patients whose tumors shrank beyond a set threshold.
At one year, 36% of patients were still free of progression, more than three times the 10% in the chemotherapy group, and about one in two patients saw their tumors shrink. In patients with MET overexpression, progression-free survival was 8.5 versus 5.6 months (hazard ratio 0.51). In patients with MET amplification it was 7.6 versus 4.2 months (hazard ratio 0.48), pointing in the same direction (exploratory analysis). The investigators reported a consistent benefit across all prespecified subgroups.
Side effects and management: be prepared for swelling
The most common side effects in the combination group were peripheral edema (swelling of the arms or legs, 49%), anemia (26%) and diarrhea (26%), mostly mild. Grade 3 or higher adverse events of any cause occurred in 64%, similar to 63% with chemotherapy, keeping in mind that patients in the combination group stayed on treatment about twice as long. Treatment-related grade 3 or higher events were less frequent than with chemotherapy (40% vs 52%).
Fourteen percent of patients stopped treatment because of side effects (8% with chemotherapy). Of 12 deaths during treatment, 9 were recorded as due to lung cancer progression or related causes, and one case of pneumonitis was judged to be treatment-related. If swelling appears, keeping a record of body weight and leg swelling to share at visits helps the care team manage it by adjusting the dose or pausing treatment. A new cough or shortness of breath should be reported promptly.
Where it is available: approved in China, under FDA review
- China: Based on another phase 3 trial (SACHI), savolitinib plus Tagrisso is approved for MET-amplified non-squamous non-small cell lung cancer that progressed after EGFR inhibitor therapy.
- United States: In September 2026, AstraZeneca submitted a new drug application to the FDA for patients with MET overexpression or amplification.
- Europe and Japan: The companies state that regulatory submissions are progressing as planned. SAFFRON is also listed in the Japan Registry of Clinical Trials (jRCT2031220420).
- Switzerland: Temporary authorization was granted based on the phase 2 SAVANNAH trial.
Even before approval, several treatments are already available after Tagrisso resistance. For example, on September 19, 2024 the U.S. FDA approved amivantamab with carboplatin and pemetrexed for patients whose disease progressed after an EGFR inhibitor (MARIPOSA-2, progression-free survival 6.3 vs 4.2 months). Approval scope and costs differ by country, so if you are considering treatment abroad, first check what is approved there. You can find other new cancer drug updates under By cancer type, and guidance on reading Japanese medical information in Other Japanese medical information.
What to check and questions for your doctor
- Can I have a repeat tissue biopsy or blood-based genetic test (liquid biopsy) to find the cause of Tagrisso resistance?
- Will the retest include MET overexpression (IHC) and MET amplification (FISH or genomic testing)?
- Depending on the results, which treatments and clinical trials are open to me?
- When should I call if my legs swell or I feel short of breath?
- Can I take it with the other medicines I am using now?
Frequently asked questions
What is the next treatment after Tagrisso resistance?
It depends on the cause of resistance. If retesting shows a MET alteration, adding a MET inhibitor as in SAFFRON may be considered. Other options include amivantamab with chemotherapy, platinum-based chemotherapy and clinical trials.
How effective was the savolitinib combination?
In SAFFRON, median overall survival was 17.8 months versus 12.9 months with chemotherapy, a 32% lower risk of death. Progression-free survival was 7.6 versus 5.4 months, and the response rate was 51% versus 27%.
What are the side effects of savolitinib?
Peripheral edema (49%), anemia (26%) and diarrhea (26%) were common and mostly mild. Recording weight and swelling helps with management, and a cough or shortness of breath should be reported to the care team right away.
Is savolitinib treatment available in Japan?
As of the source check date (2026-10-27), no Japanese approval has been announced, and the companies state that the Japanese filing is in progress. It is approved in China for MET-amplified disease and is under review in the United States.
Related: Pancreatic cancer new drug: FDA approves daraxonrasib · HER2 breast cancer maintenance: FDA approval · All cancer-type articles
Sources
- HUTCHMED — SAFFRON global Phase III data presented at ESMO Congress 2026 and simultaneously published in The New England Journal of Medicine (2026-10-25)
globenewswire.com
Checked: 2026-10-27 - The New England Journal of Medicine — Osimertinib–Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy (2026)
nejm.org
Checked: 2026-10-27 - CancerNetwork — Osimertinib/savolitinib improves survival in MET-altered EGFR-mutant NSCLC (ESMO 2026, 2026-10-25)
cancernetwork.com
Checked: 2026-10-27 - AstraZeneca — Tagrisso plus Orpathys demonstrated statistically significant and clinically meaningful improvements in PFS and OS in MET-driven EGFR-mutated lung cancer (2026-08-17)
astrazeneca.com
Checked: 2026-10-27 - ClinicalTrials.gov — NCT05261399: SAFFRON, savolitinib plus osimertinib versus platinum-based doublet chemotherapy after progression on osimertinib
clinicaltrials.gov/study/NCT05261399
Checked: 2026-10-27 - Japan Registry of Clinical Trials (jRCT) — jRCT2031220420: savolitinib plus osimertinib versus platinum-pemetrexed (SAFFRON)
jrct.niph.go.jp
Checked: 2026-10-27 - U.S. Food and Drug Administration — FDA approves amivantamab-vmjw with carboplatin and pemetrexed for NSCLC with EGFR exon 19 deletions or L858R mutations (2024-09-19)
fda.gov
Checked: 2026-10-27
Written by the FTH editorial team. Sources checked 2026-10-27 · Medical review: not applicable
This article is general information based on public sources and does not replace diagnosis or treatment. Please discuss treatment decisions with your medical team.
