Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer

Janjigian, Yelena Y. M.D.
Al-Batran, Salah-Eddin M.D.
Wainberg, Zev A. M.D.
Muro, Kei M.D., Ph.D.
Molena, Daniela M.D.
Van Cutsem, Eric M.D., Ph.D.
Hyung, Woo Jin M.D., Ph.D.
Wyrwicz, Lucjan M.D., Ph.D.
Oh, Do-Youn M.D., Ph.D.
Omori, Takeshi M.D., Ph.D.
Moehler, Markus M.D., Ph.D.
Garrido, Marcelo M.D.
Oliveira, Sulene C.S. M.D.
Liberman, Moishe M.D., Ph.D.
Oliden, Victor Castro M.D.
Smyth, Elizabeth C. M.D.
Stein, Alexander M.D.
Bilici, Mehmet M.D.
Alvarenga, Maria Lorena M.D.
Kozlov, Vadim M.D.
Rivera, Fernando M.D., Ph.D.
Kawazoe, Akihito M.D., Ph.D.
Serrano, Olivier M.Sc.
Heilbron, Eric M.D.
Negro, Alejandra Ph.D.
Kurland, John F. Ph.D.
Tabernero, Josep M.D., Ph.D.

¹Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York
²Krankenhaus Nordwest, University Cancer Center (UCT) Frankfurt, and Frankfurt Institute of Clinical Cancer Research (IKF), Frankfurt, Germany
³Department of Gastrointestinal Medical Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles
⁴Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
⁵Division of Thoracic Surgery, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York
⁶Department of Gastroenterology/Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
⁷Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
⁸Department of Oncology and Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
⁹Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, and the Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
¹⁰Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
¹¹Research Center for Immunotherapy (FZI), Johannes Gutenberg-University Clinic, Mainz, Germany
¹²Hemato-Oncology Department, SAGA Clinical Trial Center and Universidad Mayor, Santiago, Chile
¹³Clinical Oncology, Clinical Research Center, Northern Riograndense League Against Cancer, Natal, Brazil
¹⁴Division of Thoracic Surgery, Department of Surgery, Centre Hospitalier de l'Université de Montréal, Centre de Recherche du CHUM, Montréal
¹⁵National Institute of Neoplastic Diseases (INEN), Lima, Peru
¹⁶Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom
¹⁷Hematology-Oncology Practice Eppendorf (HOPE), University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
¹⁸Department of Internal Medicine, Division of Medical Oncology, Atatürk University Faculty of Medicine, Erzurum, Turkey
¹⁹Department of Clinical Oncology, Favaloro Foundation University Hospital, Buenos Aires
²⁰State Budgetary Health Care Institution, Novosibirsk Regional Clinical Oncology Dispensary, Novosibirsk, Russia
²¹Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
²²Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
²³Cytel, AstraZeneca, Paris
²⁴Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, MD
²⁵Medical Oncology Department, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona

Dr. Janjigian can be contacted at [email protected] or at Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, BAIC Rm. 1001, 300 E. 66th St., New York, NY 10065.

A complete list of investigators in the MATTERHORN trial is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on June 1, 2025, and updated on June 27, 2025, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by AstraZeneca. Dr. Janjigian's work was supported by a Cancer Center Support grant (P30 CA008748, to the Memorial Sloan Kettering Cancer Center) from the National Cancer Institute of the National Institutes of Health.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

New England Journal of Medicine 393(3):p 217-230, July 17, 2025. | DOI: 10.1056/NEJMoa2503701

ABSTRACT

BACKGROUND

Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is a standard therapy for resectable gastric and gastroesophageal junction adenocarcinomas, but recurrence rates remain high. Immunotherapy plus chemotherapy may improve outcomes.

METHODS

In a phase 3, multinational, double-blind, randomized trial, we assigned participants with resectable gastric or gastroesophageal junction adenocarcinoma, in a 1:1 ratio, to receive durvalumab at a dose of 1500 mg or placebo every 4 weeks plus FLOT for 4 cycles (2 cycles each of neoadjuvant and adjuvant therapy), followed by durvalumab or placebo every 4 weeks for 10 cycles. The primary end point was event-free survival; secondary end points included overall survival and pathological complete response.

RESULTS

A total of 474 participants were randomly assigned to the durvalumab group, and 474 to the placebo group (median follow-up, 31.5 months; interquartile range, 26.7 to 36.6). Two-year event-free survival (Kaplan-Meier estimate) was 67.4% among the participants in the durvalumab group and 58.5% among those in the placebo group (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001). Two-year overall survival was 75.7% in the durvalumab group and 70.4% in the placebo group (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], and during the period from month 12 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]). The percentage of participants with a pathological complete response was 19.2% in the durvalumab group and 7.2% in the placebo group (relative risk, 2.69 [95% CI, 1.86 to 3.90]). Adverse events with a maximum grade of 3 or 4 were reported in 340 participants (71.6%) in the durvalumab group and in 334 (71.2%) in the placebo group. The percentage of participants with delayed surgery was 10.1% and 10.8%, respectively, and the percentage with delayed initiation of adjuvant treatment was 2.3% and 4.6%.

CONCLUSIONS

Perioperative durvalumab plus FLOT led to significantly better event-free survival outcomes than FLOT alone among participants with resectable gastric or gastroesophageal junction adenocarcinoma. (Funded by AstraZeneca; MATTERHORN ClinicalTrials.gov number, NCT04592913.)

Perioperative Durvalumab in Gastric Cancer

In resectable gastric and gastroesophageal junction cancer, adding durvalumab to perioperative chemotherapy improved event-free survival and pathological complete response, with no major increase in high-grade adverse events.