Yelena Janjigian, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses the results from the phase 3 MATTERHORN study, evaluating durvalumab plus FLOT chemotherapy for patients with resectable gastric/gastroesophageal junction cancer.

In the plenary session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr Janjigian presented that durvalumab plus FLOT improved the event-free survival compared to placebo plus FLOT in this trial.

Dr Janjigian concluded this data “presents the new global standard for localized gastroesophageal adenocarcinoma, unifying how we treat this patient.” She added, “It's clear that something more than surgery needs to be done to prevent cancer recurrence, and here, a combination of durvalumab plus FLOT in the neoadjuvant setting offers this option to help suppress micro-metastasis and cure more patients.”

Transcript:

Hello, my name is Dr. Elena Jenji. I am chief of GI Oncology Service at Memorial Sloan Kettering Cancer Center in New York. At ASCO this year, in the plenary session on Sunday, June 1st, I will be presenting the results of the phase 3 MATTERHORN study.

MATTERHORN is a study that was designed to test the hypothesis that using immunotherapy early in localized disease will help improve outcomes in patients with non-metastatic gastroesophageal adenocarcinoma, irrespective of PD-L1 status. By way of background, we know that a subset of gastroesophageal cancers present with early-stage disease and surgery is the standard for these patients. We also use chemotherapy such as a 3-drug combination with Flo 5-FU, oxaliplatin, docetaxel as a standard way to prevent cancer recurrence. And that has been validated in 2 phase 3 studies in a prospective setting. What we also know is that immunotherapy helps patients live longer in metastatic disease. In the combination of chemotherapy, usually 2-drug chemotherapy, 5-FU and oxaliplatin, with drugs like pembrolizumab or nivolumab help improve survival.

And so in the phase 3 study MATTERHORN, we randomized patients globally in 1-to-1 randomization to receive durvalumab, which is another form of anti–PD-L1 therapy, with FLOT versus placebo and FLOT. These were patients with stage II to IVa tumors. Many of them were node positive clinically. Both gastric and gastroesophageal junction adenocarcinoma patients were permitted to go on the study. Patients were stratified by PD-L1 status, but they were enrolled irrespective of whether or not they were PD-L1 high or low, and by location geographically, Asia versus non-Asia, as well as clinical node-positivity.

The patients received 4 doses of FLOT with 2 doses of durvalumab, which constitutes 2 cycles —the cycles were based on the durvalumab dosing— before surgery followed by surgery, and then 4 additional doses of FLOT with 2 doses of durvalumab, followed by 10 doses of durvalumab or placebo. As I mentioned, this was a randomized, blinded, placebo-controlled study. The purpose of the study was to demonstrate the primary end point, event-free survival. This was defined as from the time of randomization to disease progression or cancer recurrence, and the secondary end point was pathologic complete response and overall survival.

The alpha of the analysis, in the statistical analysis was initially tested with an interim analysis of pathological CR [complete response] rate was met. Subsequently, the rest of the alpha was passed on to event-free survival and very little alpha was spent on overall survival. At this analysis, at the presentation at ASCO 2025 plenary presentation we're presenting event-free survival with early assessment of overall survival. And then the subsequent analysis will be the alpha; 4.99% of alpha will be passed on for the final overall survival analysis.

We've already demonstrated that pathologic complete response rate is improved with addition of durvalumab plus FLOT. The durvalumab-FLOT cohort had 19% complete response rate, meaning microscopically, there was no tumor left in the primary tumor or the lymph nodes, and the FLOT-placebo cohort had 7% complete response rate. This was a 12% improvement in pathologic complete response rate, which is clinically meaningful. But until this day, we did not know if this would translate to event-free survival.

At the ASCO plenary presentation, the event-free survival analysis and the primary endpoint was met for the study, demonstrating that durvalumab plus FLOT improved event-free survival compared to placebo plus FLOT. We’re also presenting initial overall survival analysis. Although that survival analysis is not final and the final analysis and the alpha will be based on the pre-specified by statistical plan we presented at a later date, we also demonstrated that durvalumab and flat were feasible globally in a global setting.

This was a global study with 19% of patients enrolled in Asia and that it was feasible to do before surgery. There were no major delays in operations compared to placebo Flo, and these patients globally were able to get therapy with flaw. The most common side effects of flaw therapy include diarrhea and neutropenia, and these side effects are related to chemotherapy. And overall, there were no new signals of safety in the study.

In summary, the MATTERHORN study presents the new global standard for localized gastroesophageal adenocarcinoma, unifying how we treat this patient. It's clear that something more than surgery needs to be done to prevent cancer recurrence. And here, a combination of durvalumab plus FLOT in the neoadjuvant setting offers this option to help suppress micro-metastasis and cure more patients.

Source:

Janjigian Y, Al-Batran S-E, Wainberg Z, et al. Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). Presented at 2025 ASCO Annual Meeting. May 31-June 3, 2025; Chicago, IL. Abstract LBA5