AstraZeneca’s Imfinzi-Based Regimen Shows Significant Benefit in Early Gastric and GEJ Cancers in Phase III MATTERHORN Trial
AstraZeneca has reported highly promising results from its Phase III MATTERHORN trial, showcasing the potential of its immunotherapy drug Imfinzi (durvalumab) to transform the treatment landscape for patients with resectable early-stage and locally advanced gastric and gastroesophageal junction (GEJ) cancers. The data, unveiled during the prestigious Plenary Session of the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, and concurrently published in The New England Journal of Medicine, highlighted a significant and clinically meaningful improvement in event-free survival (EFS) when Imfinzi was added to standard chemotherapy in a perioperative setting.
The MATTERHORN trial tested a novel approach to managing these aggressive gastrointestinal cancers, using a multi-phase treatment strategy. Patients received neoadjuvant (pre-surgical) treatment with Imfinzi in combination with the standard-of-care FLOT chemotherapy regimen—comprised of fluorouracil, leucovorin, oxaliplatin, and docetaxel—followed by surgery. Post-operatively, they continued on adjuvant (post-surgical) treatment with the same Imfinzi-FLOT combination and then transitioned to Imfinzi monotherapy.
This Imfinzi-based perioperative regimen was compared against perioperative chemotherapy alone in patients with resectable Stage II, III, or IVA gastric and GEJ adenocarcinoma, a patient population with a high risk of recurrence even after surgery and chemotherapy.
A Landmark Finding in Event-Free Survival
At a pre-planned interim analysis, the Imfinzi-based regimen delivered a striking 29% reduction in the risk of disease progression, recurrence, or death compared to chemotherapy alone. This outcome was reflected in an EFS hazard ratio (HR) of 0.71, with a 95% confidence interval ranging from 0.58 to 0.86 (p<0.001), demonstrating both statistical and clinical significance.
While the median EFS for patients in the Imfinzi arm had not yet been reached at the time of analysis, those in the chemotherapy-only group showed a median EFS of 32.8 months. One-year EFS rates were 78.2% in the Imfinzi-treated cohort versus 74.0% in the control group. Notably, the benefit appeared to deepen over time: at 24 months, 67.4% of patients in the Imfinzi arm remained event-free, compared to just 58.5% of those in the comparator arm. These findings suggest a durable and potentially curative benefit from adding immunotherapy to perioperative treatment in this setting.
Promising Trend Toward Overall Survival Benefit
While overall survival (OS) results were not yet mature at this interim analysis, a strong and encouraging trend emerged in favor of the Imfinzi-based regimen. The OS hazard ratio was 0.78 (95% CI 0.62–0.97; p=0.025), indicating a 22% relative reduction in the risk of death. However, this analysis did not meet the prespecified threshold for statistical significance at this stage, and OS will be formally evaluated in a future final analysis as more survival data accumulate.
Nevertheless, the early signal for OS improvement lends further weight to the potential of this treatment approach to extend lives in addition to delaying or preventing cancer recurrence.
A Paradigm-Shifting Approach in Gastric and GEJ Cancers
Dr. Yelena Y. Janjigian, MD, Chief Attending Physician of the Gastrointestinal Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York and principal investigator for the MATTERHORN study, emphasized the significance of the trial findings.
“Despite receiving curative-intent surgery and chemotherapy, patients with gastric and gastroesophageal cancers frequently develop recurrent disease,” Dr. Janjigian said. “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.”
Gastric and GEJ cancers are notoriously aggressive and often diagnosed at an advanced stage, where treatment options are limited and outcomes poor. Surgery combined with chemotherapy has been the standard approach for resectable cases, but recurrence rates remain high, underscoring the need for more effective perioperative strategies.
Imfinzi Expands Its Footprint in Early-Stage Cancers
Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer at AstraZeneca, noted the broader implications of the MATTERHORN trial results, both for patients and for the company’s ongoing immunotherapy strategy.
“This immunotherapy-based perioperative regimen has the potential to change the clinical paradigm in early gastric and gastroesophageal junction cancers based on the reduction in risk of progression, recurrence or death by nearly a third and the strong trend towards improved survival,” said Massacesi.
He added, “As the third positive trial of perioperative treatment with Imfinzi across multiple tumour types, the MATTERHORN trial further validates this approach and highlights our commitment to bringing novel therapies to early stages of disease where there is the greatest chance for cure.”
Indeed, Imfinzi has already made significant strides in earlier stages of cancer in other tumor types. The success of MATTERHORN follows previous positive outcomes from trials in non-small cell lung cancer (such as the AEGEAN study) and biliary tract cancer (TOPAZ-1), where perioperative and combination strategies have shown clinical benefit.
A Milestone for Immunotherapy in Gastrointestinal Oncology
The MATTERHORN trial represents one of the most compelling demonstrations yet of the value of checkpoint inhibitors in earlier-stage gastrointestinal cancers. Imfinzi, an anti-PD-L1 monoclonal antibody, works by blocking the interaction between PD-L1 and PD-1, thereby enhancing the immune system’s ability to recognize and destroy tumor cells. While checkpoint inhibitors have transformed the treatment of several advanced cancers, their role in earlier-stage disease—especially in the neoadjuvant and adjuvant settings—has only recently come to the forefront of oncologic research.
By integrating immunotherapy across both pre- and post-operative phases and maintaining immune activation through monotherapy after surgery, the MATTERHORN regimen offers a comprehensive immune-oncology strategy designed to reduce tumor burden, prevent micrometastatic spread, and enhance long-term tumor control.
Future Directions and Regulatory Implications
With these positive results, AstraZeneca is likely to pursue regulatory approvals for Imfinzi in the perioperative treatment of gastric and GEJ cancers. If approved, this could mark a major shift in how oncologists approach early-stage disease, moving beyond traditional chemotherapy and surgery toward a multimodal strategy anchored in immunotherapy.
Regulatory filings are expected to follow, and future updates from the MATTERHORN trial—particularly regarding overall survival and long-term safety—will be closely watched by clinicians, payers, and patients alike.
The MATTERHORN Phase III trial marks a major advancement in the treatment of resectable early-stage and locally advanced gastric and gastroesophageal junction cancers. The addition of Imfinzi to standard chemotherapy in a perioperative setting significantly delayed disease progression and recurrence, with early signs of improving overall survival. These findings have the potential to redefine the standard of care for a patient population historically underserved by therapeutic advances. With immunotherapy continuing to make headway into earlier lines of treatment, the results of MATTERHORN underscore AstraZeneca’s leadership in immune-oncology and its commitment to improving cancer outcomes at the stages where the possibility of cure is greatest.
