Inflammation and Mutational Burden Differentially Associated With Nivolumab or Ipilimumab Combination Efficacy in Colorectal Cancer

Authors

Ming Lei
Michael J Overman
Jin Yao
Thierry André
Sara Lonardi
Heinz-Josef Lenz
Massimo Aglietta
Fabio Gelsomino
Ray McDermott
Ka Yeung Mark Wong
Michael A Morse
Eric Van Cutsem
Alain Hendlisz
Dana B Cardin
Bart Neyns
Andrew Hill
Anuradha Krishnamurthy
Franklin Chen
Samith Kochuparambil
Robert R Jenq
Sandzhar Abdullaev
Beilei He
Ruslan Novosiadly
Scott Kopetz

Language

English

Publication Date

10-6-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-63960-8

PMID

41053075

PMCID

PMC12501054

PubMedCentral® Posted Date

10-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

Keywords

Humans, Ipilimumab, Nivolumab, Colorectal Neoplasms, Microsatellite Instability, Antineoplastic Combined Chemotherapy Protocols, Inflammation, Mutation, Biomarkers, Tumor, Male, Female, Treatment Outcome, Antineoplastic Agents, Immunological, Colorectal cancer, Predictive markers

Published Open-Access

yes

Recommended Citation

Lei, Ming; Overman, Michael J; Yao, Jin; et al., "Inflammation and Mutational Burden Differentially Associated With Nivolumab or Ipilimumab Combination Efficacy in Colorectal Cancer" (2025). Faculty, Staff and Student Publications. 6020.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6020