Behind the MATTERHORN Trial of Durvalumab/FLOT in Gastric/GEJ Cancer

The phase 3 MATTERHORN study (NCT04592913) was designed to assess durvalumab (Imfinzi) plus 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) neoadjuvant and adjuvant treatment, followed by single-agent durvalumab as a treatment for patients with resectable gastric and gastroesophageal junction (GEJ) cancers. The combination received FDA approval in November 2025.^1,2

In the trial, patients were given 1500 mg of durvalumab for patients who weighed 30 kg or more every 4 weeks with chemotherapy for up to 4 cycles, followed by 1500 mg as a single agent every 4 weeks for up to 10 cycles. For patients with a body weight of less than 30 kg, the recommended durvalumab dose was 20 mg/kg with chemotherapy every 4 weeks for up to 4 cycles and 20 mg/kg as a single agent every 4 weeks for up to 10 cycles.

Yelena Y. Janjigian, MD, an investigator on the MATTERHORN study, spoke with CancerNetwork® about the FDA approval, as well as the design and impetus behind the study. Furthermore, she highlighted important end points that were pivotal to the trial’s results.

Janjigian is chief of the Gastrointestinal Oncology Service and Carroll and Milton Petrie Chair at Memorial Sloan Kettering Cancer Center.

Transcript:

MATTERHORN is a global phase 3 study that was designed to answer the question of whether perioperative immunotherapy with durvalumab, compared with placebo, can improve outcomes in combination with standard perioperative chemotherapy, which is a triplet drug combination, FLOT, 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel. We designed MATTERHORN with a question in mind: can gastroesophageal adenocarcinomas and gastric cancer globally be treated with the same regimen? Is FLOT in combination with anti–PD-1 therapy with durvalumab safe? Can it improve efficacy?

The 3 points of efficacy that we focused on [included] the primary end point, which is event-free survival in the intent-to-treat population. We looked at the early readout of efficacy, which is the pathological complete response rate. We looked at the key secondary end point of overall survival. This was the first study to try to answer that question using FLOT, which is the modern backbone regimen, and treating patients irrespective of PD-L1 status. All over the world, patients were [randomly assigned] in a 1:1 fashion to receive durvalumab with FLOT or placebo with FLOT before and after surgery, followed by additional cycles of durvalumab by itself or pembrolizumab by itself for up to a year of therapy. That was the point of MATTERHORN: to bring immunotherapy to the perioperative setting. We know that in the metastatic setting, immunotherapy and drugs with anti–PD-1 blockade improve survival. We wanted to improve outcomes in early-stage disease [as well].

References

1. Tabernero J, Al-Batran S-E, Wainberg ZAA, et al. Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: a randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Presented at: ESMO 2025 Congress; October 17–20, 2025; Berlin, Germany. Abstract LBA81.
2. FDA approves durvalumab for resectable gastric or gastroesophageal junction adenocarcinoma. News release. FDA. November 25, 2025. Accessed December 23, 2025. https://tinyurl.com/mrsfxta8