Tagrisso, Orpathys Cut Progression or Death Risk 45% in Lung Cancer

Positive results from the SAFFRON Phase III trial showed Tagrisso (osimertinib) plus Orpathys (savolitinib) demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) versus doublet platinum-based chemotherapy in patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Patients in the trial had tumours with high levels of MET overexpression or amplification and had progressed on prior treatment with Tagrisso.

These results will be presented today during the Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain (abstract #LBA6).¹ They were also simultaneously published in The New England Journal of Medicine.

Results showed Tagrisso plus Orpathys reduced the risk of disease progression or death by 45% compared to chemotherapy (based on a PFS hazard ratio [HR] of 0.55; 95% confidence interval [CI] 0.42-0.72; p<0.001). Median PFS as assessed by blinded independent central review (BICR) was 7.6 months for Tagrisso plus Orpathys versus 5.4 months for the comparator arm. An estimated 36% of patients treated with the combination were progression-free at one year compared to 10% in the comparator arm. Importantly, the PFS benefit observed was consistent across all prespecified subgroups, including patients whose tumours had MET-overexpression or MET-amplification.

Results for the key secondary endpoint of OS showed Tagrisso plus Orpathys reduced the risk of death by 32% versus chemotherapy (OS HR 0.68; 95% CI 0.50-0.91; p=0.010). Tagrisso plus Orpathys extended median OS by 4.9 months versus the comparator arm (17.8 versus 12.9 months). An estimated 70% of patients treated with the combination were alive at one year compared to 53% in the comparator arm.

Professor Shun Lu, Director of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine and principal investigator of the trial, said: "These results have the potential to establish a new global standard of care for the third of patients with EGFR-mutated non-small cell lung cancer experiencing high levels of MET-driven resistance after osimertinib. There are currently no well-tolerated, oral, biomarker-directed treatment options to address this frequent driver of disease progression. Osimertinib plus savolitinib significantly extended median overall survival by nearly five months in this later-line setting, establishing a new clinical benchmark and reinforcing the critical need for MET testing to guide patient care."

Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "These data show combining Orpathys with backbone therapy Tagrisso directly addresses MET-driven resistance while maintaining EGFR suppression, building on the established efficacy, safety and central nervous system protection of Tagrisso. With the potential to become the first biomarker-directed, all-oral treatment option in this setting, this combination further strengthens our leadership in EGFR-mutated lung cancer and reflects our strategy of matching the right therapy to the underlying drivers of disease at every stage."

Johnny Cheng, Acting Chief Executive Officer and Chief Financial Officer, HUTCHMED, said: "These data from SAFFRON mark a decisive step forward in targeting MET-driven resistance-a longstanding challenge in EGFR-mutated lung cancer. Precision inhibition with Orpathys alongside Tagrisso offers a meaningful, all-oral option for patients with disease progression. We are delighted to see that our partnership with AstraZeneca continues to deliver impactful innovations that have the potential to redefine standard of care and improve outcomes for patients globally."

Summary of PFS and OS results: SAFFRONⁱ

The safety profile for Tagrisso plus Orpathys was manageable and consistent with the known profiles of each medicine, and there were no new safety concerns. Grade 3 or higher treatment-emergent adverse events from all causes occurred in 64% of patients treated with Tagrisso plus Orpathys and 63% of patients in the comparator arm. Median total duration of treatment exposure was more than twice as long for Tagrisso plus Orpathys (8.5 months) compared with the comparator arm (3.5 months).

Based on the SAFFRON Phase III trial results, a New Drug Application (NDA) for Tagrisso plus Orpathys was submitted to the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic NSCLC whose tumors have MET overexpression or amplification and who had disease progression on or after an EGFR-tyrosine kinase inhibitor (TKI) therapy. Tagrisso plus Orpathys is approved in China for patients with locally advanced or metastatic EGFRm-positive non-squamous NSCLC with MET amplification after disease progression on EGFR-TKI therapy based on the SACHI Phase III trial.

Results from the SANOVO Phase III trial evaluating Tagrisso plus Orpathys in treatment-naive patients in China with EGFRm locally advanced or metastatic NSCLC and MET overexpression will be presented tomorrow during a Proffered Paper session at the ESMO Congress (abstract #LBA69).²

Orpathys is being jointly developed by AstraZeneca and HUTCHMED and commercialised by AstraZeneca.

Notes

NSCLC and MET aberrations
Lung cancer is the leading cause of cancer death globally, accounting for almost one in five (19%) cancer deaths.^3-4 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% of patients diagnosed with NSCLC.⁵ Approximately 75% of NSCLC patients are diagnosed with advanced disease.⁶ Additionally, about 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia, have EGFRm NSCLC.⁷

MET is a tyrosine kinase receptor that has an essential role in normal cell development.⁸ MET overexpression or amplification can lead to tumour growth and the metastatic progression of cancer cells.^8-9 Approximately one in three patients' tumours will develop high levels of MET overexpression or amplification (IHC3+>90% and FISH10+) after progression on a third-generation EGFR-TKI.¹⁰ ​

SAFFRON
SAFFRON is a randomised, open-label, multi-centre, global Phase III trial studying the efficacy of Orpathys (300mg twice daily) added to Tagrisso (80mg once daily) versus doublet platinum-based chemotherapy in 338 patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease progressed following 1st- or 2nd-line treatment with Tagrisso. The trial enrolled patients in 230 centres across 29 countries, including in North America, Europe, South America and Asia. The primary endpoint is PFS and key secondary endpoints include OS and objective response rate.

Patients were prospectively selected for SAFFRON 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 if cancer cells have a particular protein or marker on their surface, and fluorescence in situ hybridisation (FISH), which detects a specific DNA sequence from cancer cells.

Orpathys
Orpathys (savolitinib) is an oral, potent and highly selective MET-TKI that has demonstrated clinical activity in advanced solid tumours. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

Orpathys is approved in China for the treatment of adult patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alteration, representing the first selective MET inhibitor approved in China. Orpathys also received a conditional approval in China for the treatment of patients with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with MET amplification who have failed at least two prior systemic treatments.

Orpathys in combination with Tagrisso was granted a temporary authorisation in Switzerland for the treatment of patients with locally advanced or metastatic EGFRm NSCLC and high levels of MET overexpression or amplification who progressed on prior treatment with Tagrisso. This was based on results from the global SAVANNAH Phase II trial.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including the treatment of central nervous system metastases. Tagrisso (40mg and 80mg QD oral tablets) has been used to treat more than one million patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

Tagrisso is approved as monotherapy in more than 120 countries including the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, adjuvant treatment of early-stage EGFRm NSCLC and locally advanced, unresectable NSCLC following platinum-based chemoradiation therapy. Tagrisso is also approved in combination with chemotherapy in more than 80 countries, including the US, EU, China and Japan, for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC, and it is the only targeted therapy shown to improve patient outcomes across all stages of the disease.

In late-stage disease, Tagrisso demonstrated improved outcomes as monotherapy in the FLAURA Phase III trial and in combination with chemotherapy in the FLAURA2 Phase III trial. Tagrisso is also being investigated in this setting in combination with Datroway (datopotamab deruxtecan or Dato-DXd) in the TROPION-Lung14 and TROPION-Lung15 Phase III trials.

Tagrisso also showed improved outcomes in early-stage disease in the NeoADAURA and ADAURA Phase III trials and in locally advanced stages in the LAURA Phase III trial. As part of AstraZeneca's ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company's comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso and Iressa (gefitinib); Imfinzi and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and Datroway in collaboration with Daiichi Sankyo; Orpathys in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Disease, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca's innovative medicines are sold in more than 125 countries and used by millions of patients worldwide.