Results from a planned interim analysis of the pivotal Phase III MATTERHORN trial (NCT04592913) show Imfinzi (durvalumab) plus standard-of-care chemotherapy produced a significant boost in event-free survival (EFS) among patients with resectable gastric and gastroesophageal junction (GEJ) cancers.^1,2

MATTERHORN Trial Establishes First EFS Benefit with Immunotherapy in Resectable Gastric and GEJ Cancers

Trial data, presented at ASCO 2025 and published in The New England Journal of Medicine (NEJM), demonstrate that Imfinzi is the first immunotherapy to achieve statistically significant EFS in a global Phase III trial in this patient population, according to the trial investigators.³

“Despite receiving curative-intent surgery and chemotherapy, patients with gastric and gastroesophageal cancers frequently develop recurrent disease,” MATTERHORN principal investigator Yelena Y. Janjigian, MD, chief attending physician of Gastrointestinal Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, said in a press release. “Despite receiving curative-intent surgery and chemotherapy, patients with gastric and gastroesophageal cancers frequently develop recurrent disease. Results from the MATTERHORN trial showed that more than two-thirds of patients treated with a durvalumab-based perioperative regimen had not experienced a recurrence or were progression-free after two years. This new treatment approach should become the new standard of care in this setting based on these results.”¹

Key Efficacy Outcomes: Event-Free Survival and Overall Survival Trends

Imfinzi is a selective, high-affinity human IgG1 monoclonal antibody that attaches to PD-L1 and blocks interactions with PD-1 and CD80 on activated T cells. Current FDA-approved indications for Imfinzi include for the treatment of unresectable, stage III non-small cell lung cancer (NSCLC) in patients with disease that has not progressed following chemoradiation therapy; for the treatment of extensive-stage small-cell lung cancer; combined with a limited course of Imjudo (tremelimumab) and chemotherapy to treat metastatic NSCLC; in combination with gemcitabine plus cisplatin to treat locally advanced or metastatic biliary tract cancer; and in combination with Imjudo to treat unresectable hepatocellular carcinoma. Most recently, Imfinzi was approved in combination with chemotherapy for adult patients with resectable early-stage (IIA-IIIB) NSCLC without EGFR mutations or ALK rearrangements.

“The FLOT4 trial established perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) as treatment for locally advanced resectable gastric or gastroesophageal junction adenocarcinoma; FLOT was associated with better overall survival and disease-free survival outcomes than epirubicin and cisplatin plus either fluorouracil or capecitabine,” the study authors wrote in NEJM. “Despite this result, recurrence rates with FLOT remain high. The combination of anti–programmed death ligand 1 (PD-L1) therapy and chemotherapy has shown encouraging outcomes and is approved for the treatment of metastatic gastric and gastroesophageal junction adenocarcinomas. Durvalumab, an anti–PD-L1 antibody, is approved for the treatment of a range of solid tumors.”³

Study Design and Global Scope of the Phase III MATTERHORN Trial

• The randomized, double-blind, placebo-controlled, multi-center, global MATTERHORN trial analyzed neoadjuvant administration of Imfinzi plus FLOT in patients with resectable stage II-IVA gastric and GEJ cancers. Participants were enrolled at 176 centers across 20 countries, including the United States, Canada, Europe, South America, and Asia.
• Investigators randomly assigned 948 patients in a 1:1 ratio to receive Imfinzi at a fixed dose of 1500 mg plus FLOT chemotherapy (n = 474) or placebo plus FLOT (n = 474) administered in two cycles each of neoadjuvant and adjuvant therapy followed by Imfinzi or placebo every four weeks for 10 cycles. 
• The trial’s primary endpoint was EFS, with key secondary endpoints that included pathologic complete response (pCR) rate and overall survival (OS).

Imfinzi Plus FLOT Chemotherapy Significantly Improves Event-Free Survival in Resectable Gastric and GEJ Cancers

• The latest findings from the interim analysis show a two-year EFS Kaplan–Meier estimate of 67.4% among patients administered the Imfinzi combination compared to 58.5% among patients in the placebo cohort (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001).
• The two-year OS rate was 75.7% among patients administered the Imfinzi combination compared to 70.4% among patients in the placebo cohort (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], as well as from 12 months and onward, 0.67 [95% CI, 0.50 to 0.90]; P=0.03 by a stratified log-rank test [exceeding the significance threshold of P<0.0001]). These OS rates have not reached the level of statistical significance.

Durability of Response and Safety Profile Across Treatment Arms

• Data from the trial released in October 2023 showed a statistically significant and clinically meaningful improvement in pCR with the Imfinzi combination compared to neoadjuvant chemotherapy alone in this patient population.
• Investigators observed a pCR rate of 19% with the Imfinzi combination compared to 7% with chemotherapy alone as determined by blinded independent central review (odds ratio [OR] 3.08; p<0.00001).
• Rates of either complete or near-complete responses were 27% in patients treated with the Imfinzi combination compared to 14% with chemotherapy alone.⁴
• In terms of safety, adverse events with a maximum grade of 3 or 4 occurred in 71.6% of patients administered the Imfinzi combination compared to 71.2% in the placebo cohort.
• The percentage of patients with delayed surgery was 10.1% in the Imfinzi cohort compared to 10.8% in the placebo cohort and the percentage with delayed initiation of adjuvant treatment was 2.3% in the Imfinzi cohort compared to 4.6% in the placebo cohort.

Global Relevance and Future Impact on Perioperative Treatment Standards

“A key strength of the MATTERHORN trial was its global reach, which reflected the global population with gastric or gastroesophageal junction adenocarcinoma eligible for perioperative FLOT, including participants across Europe, the Americas, and East Asia with stage II to IVA disease,” the study authors wrote. “Of note, the median event-free survival in the placebo group of the MATTERHORN trial (32.8 months) was consistent with the median disease-free survival in the FLOT group of the FLOT4 trial (30 months). Recent studies suggest that event-free survival is a good surrogate end point for overall survival in patients with gastric or gastroesophageal junction adenocarcinoma in the context of neoadjuvant therapy with or without adjuvant therapy.”³

References

1. Imfinzi regimen reduced risk of progression, recurrence or death by 29% in early-stage gastric cancer vs. chemotherapy alone in MATTERHORN Phase III trial. News release. AstraZeneca. June 1, 2025. Accessed June 4, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/imfinzi-regimen-reduced-risk-of-progression-recurrence-or-death-by-29-in-early-stage-gastric-cancer-vs-chemotherapy-alone-in-matterhorn-phase-iii-trial.html#!

2. Assessing Durvalumab and FLOT Chemotherapy in Resectable Gastric and Gastroesophageal Junction Cancer. ClinicalTrials.gov. Updated April 3, 2025. Accessed June 4, 2025. https://clinicaltrials.gov/study/NCT04592913

3. Janjigian Y., et al. N Engl J Med 2025; Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. DOI: 10.1056/NEJMoa2503701.

4. Imfinzi plus chemotherapy more than doubled pathologic complete response rate in resectable early-stage gastric and gastroesophageal junction cancers versus chemotherapy alone. News release. AstraZeneca. October 20, 2023. Accessed June 4, 2025. https://www.astrazeneca.com/media-centre/press-releases/2023/imfinzi-plus-chemotherapy-doubled-pathologic-complete-response-rate-resectable-early-stage-gastric-gastroesophageal-junction-cancers-vs-chemotherapy.html