Document Type
Journal Article
Publication Title
Nature Medicine
Publisher
Nature
School
Exercise Medicine Research Institute
Publication Unique Identifier
10.1038/s41591-025-03575-0
Funders
Bristol Myers Squibb / Ono Pharmaceutical Co.
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
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Shitara, K., Janjigian, Y. Y., Ajani, J., Moehler, M., Yao, J., Wang, X., ... & Lei, M. (2025). Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: Exploratory biomarker analyses of a randomized phase 3 trial. Nature Medicine. Advance online publication. https://doi.org/10.1038/s41591-025-03575-0