On October 17, 2025 Astrazeneca reported positive results from the MATTERHORN Phase III trial showed perioperative treatment with Imfinzi (durvalumab) in combination with standard-of-care FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS) versus chemotherapy alone. Patients were treated with neoadjuvant Imfinzi in combination with chemotherapy before surgery, followed by adjuvant Imfinzi in combination with chemotherapy, then Imfinzi monotherapy. The trial evaluated this regimen versus perioperative chemotherapy alone for patients with resectable, early-stage and locally advanced (Stages II, III, IVA) gastric and gastroesophageal junction (GEJ) cancers.
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These results will be presented today in a Proffered Paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2025 in Berlin, Germany (abstract #LBA81).
In the final OS analysis, results showed the Imfinzi and FLOT perioperative regimen reduced the risk of death by 22% compared with chemotherapy alone (based on a hazard ratio [HR] of 0.78; 95% confidence interval [CI] 0.63-0.96; p=0.021). Median OS was not yet reached for either arm. An estimated 69% of patients treated with the Imfinzi-based regimen were alive at three years compared with 62% in the FLOT-only arm.
Josep Tabernero, MD, PhD, head of the Medical Oncology Department at the Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology (VHIO) in Barcelona, Spain, and principal investigator in the trial, said: "The MATTERHORN data are transformative for patients with early gastric and gastroesophageal cancers, where recurrence is common and long-term prognosis remains poor despite curative-intent surgery and chemotherapy. Nearly seven in 10 patients treated with the durvalumab-based perioperative regimen were alive at three years, and the survival benefit was observed regardless of PD-L1 status. With results like these, this novel treatment should become the new standard of care in this curative-intent setting."
Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "Imfinzi’s overall survival results, which demonstrate a 22 per cent reduction in the risk of death, could change the treatment paradigm for patients with early gastric and gastroesophageal cancers. This is the first immunotherapy-based perioperative regimen to significantly extend survival in this setting, and these results illustrate our strategy to move novel treatments into early-stage cancers where cure is possible."
Summary of OS results: MATTERHORN
Imfinzi-based regimen
(n=474)
Chemotherapy regimen
(n=474)
OS i,ii
mOS (in months)iii
NR (NR-NR)
NR (NR-NR)
HR (95% CI) iv
0.78 (0.63-0.96)
Stratified log-rank p-value
0.021
Number of deaths, n (%)
160 (33.8)
192 (40.5)
Data maturity
37.1%
OS rate at 18 months, %iii
81.1
77.1
OS rate at 24 months, %iii
75.5
70.4
OS rate at 36 months, %iii
68.6
61.9
OS, PD-L1 TAP ≥1% (n)v
426
427
Number of deaths, n (%)
143 (33.6%)
172 (40.3%)
mOS (in months)
NR (NR-NR)
NR (NR-NR)
HR (95% CI)
0.79 (0.63-0.99)
OS, PD-L1 TAP <1% (n)v
48
47
Number of deaths, n (%)
17 (35.4%)
20 (42.6%)
mOS (in months)
NR (43.66-NR)
NR (21.72-NR)
HR (95% CI)
0.79 (0.41-1.50)
i. OS data cut-off date was 1 September 2025
ii. Median follow-up duration for OS in all subjects at data cut-off: 39.6 months for Imfinzi plus FLOT and 38.6 months for placebo plus FLOT
iii. Calculated by Kaplan–Meier method
iv. The analysis was performed using a stratified Cox proportional hazards model, adjusting for geographic region, clinical lymph node status and PD-L1 expression status
v. TAP, Tumour area positivity
Significance threshold p <0.0499
NR, not yet reached
Results from an additional analysis of the association between pathologic outcomes and event-free survival (EFS) in MATTERHORN demonstrated that any degree of pathologic response was associated with improved EFS in the Imfinzi arm versus the comparator arm (pathologic complete response [pCR] HR 0.29; 95% CI, 0.08-0.96; major pathologic response [MPR] HR 0.32; 95% CI, 0.15-0.68); any pathologic response: HR 0.60; 95% CI, 0.46-0.79). Additionally, EFS was improved regardless of pathologic lymph node status at the time of surgery (no nodal involvement: HR 0.74; 95% CI, 0.46-1.18; nodal involvement: HR 0.77; 95% CI, 0.58-1.02).
In a previously reported interim analysis for the key primary endpoint of EFS, patients treated with the Imfinzi-based perioperative regimen showed a 29% reduction in the risk of disease progression, recurrence or death versus chemotherapy alone (based on an EFS hazard ratio [HR] of 0.71; 95% confidence interval [CI] 0.58-0.86; p<0.001). The safety profile for Imfinzi and FLOT chemotherapy was consistent with the known profiles of each medicine, and the percentage of patients that completed surgery was similar compared to chemotherapy alone. Grade 3 or higher adverse events due to any cause were similar between the two arms.
Notes
Gastric and gastroesophageal junction cancers
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth-highest leading cause of cancer mortality.1 Nearly one million new patients were diagnosed with gastric cancer in 2022, with approximately 660,000 deaths reported globally.1 In many regions, its incidence has been increasing in patients younger than 50 years old, along with other gastrointestinal (GI) malignancies.2 In 2024, there were approximately 43,000 drug-treated patients in the US, European Union (EU), and Japan with early-stage and locally advanced gastric or GEJ cancer.3 Approximately 62,000 patients in these regions are expected to be newly diagnosed in this setting by 2030.4
GEJ cancer is a type of gastric cancer that arises from and spans the area where the oesophagus connects to the stomach.5
Disease recurrence is common in patients with resectable gastric cancer despite undergoing surgery with curative intent and treatment with neoadjuvant/adjuvant chemotherapy.6 Approximately one in four patients with gastric cancer who undergo surgery develop recurrent disease within one year, and the five-year survival rate remains poor, with less than half of patients alive at five years.6-7
MATTERHORN
MATTERHORN is a randomised, double-blind, placebo-controlled, multi-centre, global Phase III trial evaluating Imfinzi as perioperative treatment for patients with resectable Stage II-IVA gastric and GEJ cancers. Perioperative therapy includes treatment before and after surgery, also known as neoadjuvant/adjuvant therapy. In the trial, 948 patients were randomised to receive a 1500mg fixed dose of Imfinzi plus FLOT chemotherapy or placebo plus FLOT chemotherapy every four weeks for two cycles prior to surgery. This was followed by Imfinzi or placebo every four weeks for up to 12 cycles after surgery (including two cycles of Imfinzi or placebo plus FLOT chemotherapy and 10 additional cycles of Imfinzi or placebo monotherapy).
In the MATTERHORN trial, the primary endpoint is EFS, defined as time from randomisation until the date of one of the following events (whichever occurred first): RECIST (version 1.1, per blinded independent central review assessment) progression that precludes surgery or requires non-protocol therapy during the neoadjuvant period; RECIST progression/recurrence during the adjuvant period; non-RECIST progression that precludes surgery or requires non-protocol therapy during the neoadjuvant period or discovered during surgery; progression/recurrence confirmed by biopsy post-surgery; or death due to any cause. Key secondary endpoints include pathologic complete response rate, defined as the proportion of patients who have no detectable cancer cells in resected tumour tissue following neoadjuvant therapy, and OS. The trial enrolled participants in 176 centres in 20 countries, including in the US, Canada, Europe, South America and Asia.
Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.
In GI cancer, Imfinzi is approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer (BTC) and in combination with Imjudo (tremelimumab) in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU.
In addition to its indications in GI cancers, Imfinzi is the global standard of care based on OS in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy (CRT). Additionally, Imfinzi is approved as a perioperative treatment in combination with neoadjuvant chemotherapy in resectable NSCLC, and in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC. Imfinzi is also approved for limited-stage small cell lung cancer (SCLC) in patients whose disease has not progressed following concurrent platinum-based CRT; and in combination with chemotherapy for the treatment of extensive-stage SCLC.
Perioperative Imfinzi in combination with neoadjuvant chemotherapy is approved in the US, EU, Japan and other countries for patients with muscle-invasive bladder cancer based on results from the NIAGARA Phase III trial. Additionally, in May 2025, Imfinzi added to Bacillus Calmette-Guérin induction and maintenance therapy met the primary endpoint of disease-free survival for patients with high-risk non-muscle-invasive bladder cancer in the POTOMAC Phase III trial.
Imfinzi in combination with chemotherapy followed by Imfinzi monotherapy is approved as a 1st-line treatment for primary advanced or recurrent endometrial cancer (mismatch repair deficient disease only in the US and EU). Imfinzi in combination with chemotherapy followed by Lynparza (olaparib) and Imfinzi is approved for patients with mismatch repair proficient advanced or recurrent endometrial cancer in the EU and Japan.
Since the first approval in May 2017, more than 414,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with NSCLC, bladder cancer, breast cancer, ovarian cancer and several GI cancers.
(Press release, AstraZeneca, OCT 17, 2025, View Source [SID1234656741])