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

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.

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Publication Details

Journal
Nature Medicine
Published
2025-03-07
DOI
https://doi.org/10.1038/s41591-025-03575-0
Citations
18
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
18.82

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article

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

Tomasz Skoczylas, Parul Doshi, Kynan Feeney, Aparna Chhibber et al.
18 citations
Nature Medicine
Cancer Immunotherapy and Biomarkers
18.82
article

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

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

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.

Nature MedicineVol. 31(5)
Universidad Mayor (CL), Universidad de La Frontera (CL), Edith Cowan University (AU), Medical University of Lublin (PL), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Sun Yat-sen University (CN), Pontificia Universidad Católica de Chile (CL), Eli Lilly (United States) (US), Johannes Gutenberg University Mainz (DE), National and Kapodistrian University of Athens (GR), Peking University (CN), Cornell University (US), Fudan University (CN), Princess Margaret Cancer Centre (CA), Bristol-Myers Squibb (United States) (US), Hospital de Câncer de Barretos (BR), Peking University Cancer Hospital (CN), Zhongshan Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Bristol-Myers Squibb (Sweden) (SE), Fundación Arturo López Pérez (CL), Gilead Sciences (United States) (US), National Cancer Center Hospital East (JP), University Hospital Cologne (DE), Daiichi Sankyo (United States) (US), Japanese Foundation For Cancer Research (JP), Nagoya University (JP)
Bristol-Myers Squibb, Ono Pharmaceutical
Good health and well-being
Openalex Percentile: Top 1%
Cancer Immunotherapy and Biomarkers
18.82
DOIOpen Access PDFOpenAlex
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