Patients with operable gastric or gastroesophageal junction cancer who received perioperative durvalumab (Imfinzi) along with a standard combination chemotherapy regimen lived longer without disease progression, recurrence or related complications, according to study results presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine.

“Despite advances in treatment and biomarker development, cure rates for early-stage gastroesophageal cancer remain below 50%, with most recurrences occurring within two years of surgery,” lead study author Yelena Janjigian, MD, of Memorial Sloan Kettering Cancer Center, said in an ASCO news release. “MATTERHORN is the first global, randomized Phase III trial to show improved event-free survival with an immunotherapy-based regimen in resectable gastric and gastroesophageal junction cancers. The use of immunotherapy in earlier-stage cancers, as demonstrated in this perioperative approach with durvalumab, can reduce the risk of recurrence and improve cure rates.”

Gastric cancer is the fifth leading cause of cancer-related death worldwide. Gastroesophageal junction cancer affects the area where the esophagus connects to the stomach. Standard treatment in the United States involves a chemotherapy regimen of 5-fluorouracil, leucovorin, oxaliplatin and docetaxel—dubbed FLOT—before and after surgery. Durvalumab is a PD-L1 checkpoint inhibitor that helps the immune system fight cancer. Immune checkpoint inhibitors are already approved for more advanced unresectable (inoperable) gastric and gastroesophageal junction cancer.

The MATTERHORN trial, funded by AstraZeneca, evaluated whether adding perioperative durvalumab to FLOT chemotherapy could improve outcomes for patients with previously untreated stage II, III or IVA resectable gastric or gastroesophageal junction cancer. The study included 948 patients in Europe (53%), Asia (19%), South America (19%) and North America (9%). More than two thirds were men, and the median age was 62 years.

The participants were randomly assigned to receive durvalumab or a placebo plus FLOT chemotherapy before and after surgery, followed by durvalumab or the placebo alone.

Patients in the durvalumab plus FLOT group saw a statistically significant 29% improvement in event-free survival (EFS)—meaning time without cancer recurrence, progression or related complications—compared with the placebo plus FLOT group.

At 12 months, the EFS rate in the durvalumab group was 78%, compared to 74% in the placebo group. At two years, there was a larger difference, 67% versus 59%, respectively. The median EFS time was 32.8 months in the placebo group, but it was not yet reached in the durvalumab group because more than half of the patients had not yet experienced recurrence, progression or complications.  

Two-year overall survival rates were 76% in the durvalumab group versus 70% in the placebo group. The median overall survival time was 47.2 months in the placebo group, but again, this endpoint was not yet reached in the durvalumab group because a majority were still alive; overall survival follow-up is ongoing.

More than twice as many patients in the durvalumab group experienced a pathological complete response compared with the placebo group (19% versus 7%).

Severe (grade 3 or 4) adverse events were common, with similar rates in the durvalumab and placebo groups (72% and 71%, respectively). The most common side effects in the durvalumab plus FLOT group were diarrhea, nausea, neutropenia (low white blood cell count), hair loss and decreased appetite. Adding durvalumab did not delay surgery or any additional treatments.

“The pace of therapeutic advances in upper gastrointestinal cancers has accelerated in recent years. Now, the MATTERHORN trial shows that perioperative treatment with FLOT plus durvalumab is better than FLOT alone in reducing the risk of recurrence,” said ASCO gastrointestinal cancer expert Pamela Kunz MD, PhD, of Smilow Cancer Hospital and Yale Cancer Center. “This trial defines a new paradigm for patients with early-stage and locally advanced gastric and gastroesophageal junction cancers and shows the benefits of giving our best treatments earlier.”

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