Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: Exploratory biomarker analyses of a randomized phase 3 trial

Authors

Kohei Shitara
Yelena Y. Janjigian
Jaffer Ajani
Markus Moehler
Jin Yao
Xuya Wang
Aparna Chhibber
Dimple Pandya
Lin Shen
Marcelo Garrido
Carlos Gallardo
Lucjan Wyrwicz
Kensei Yamaguchi
Tomasz Skoczylas
Arinilda Bragagnoli
Tianshu Liu
Michael Schenker
Patricio Yañez
Ruben Kowalyszyn
Michalis Karamouzis
Thomas Zander
Kynan Feeney, Edith Cowan UniversityFollow
Elena Elimova
Parul Doshi
Mingshun Li
Ming Lei

Document Type

Journal Article

Publication Title

Nature Medicine

Publisher

Nature

School

Exercise Medicine Research Institute

Funders

Bristol Myers Squibb / Ono Pharmaceutical Co.

Comments

Shitara, K., Janjigian, Y. Y., Ajani, J., Moehler, M., Yao, J., Wang, X., Chhibber, A., Pandya, D., Shen, L., Garrido, M., Gallardo, C., Wyrwicz, L., Yamaguchi, K., Skoczylas, T., Bragagnoli, A., Liu, T., Schenker, M., Yañez, P., Kowalyszyn, R., . . . Lei, M. (2025). Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: Exploratory biomarker analyses of a randomized phase 3 trial. Nature Medicine, 31, 1519-1530. https://doi.org/10.1038/s41591-025-03575-0

Abstract

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein–Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

DOI

10.1038/s41591-025-03575-0

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