Inflammation and mutational burden differentially associated with nivolumab or ipilimumab combination efficacy in colorectal cancer

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 and Scott Kopetz ()
Additional contact information
Ming Lei: Bristol Myers Squibb
Michael J. Overman: University of Texas MD Anderson Cancer Center
Jin Yao: Bristol Myers Squibb
Thierry André: Sorbonne Université
Sara Lonardi: Veneto Institute of Oncology IOV-IRCCS
Heinz-Josef Lenz: University of Southern California Norris Comprehensive Cancer Center
Massimo Aglietta: IRCCS - Istituto di Candiolo
Fabio Gelsomino: University Hospital of Modena
Ray McDermott: St Vincent’s University Hospital and Cancer Trials Ireland
Ka Yeung Mark Wong: Westmead Hospital
Michael A. Morse: Duke University Medical Center
Eric Van Cutsem: University Hospitals Gasthuisberg/Leuven and KU Leuven
Alain Hendlisz: Institut Jules Bordet
Dana B. Cardin: Vanderbilt University Medical Center
Bart Neyns: Universitair Ziekenhuis Brussel
Andrew Hill: Tasman Oncology Research Ltd.
Anuradha Krishnamurthy: University of Pittsburgh Cancer Institute
Franklin Chen: Novant Health Cancer Institute
Samith Kochuparambil: Minnesota Oncology
Robert R. Jenq: University of Texas MD Anderson Cancer Center
Sandzhar Abdullaev: Bristol Myers Squibb
Beilei He: Bristol Myers Squibb
Ruslan Novosiadly: Bristol Myers Squibb
Scott Kopetz: University of Texas MD Anderson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63960-8

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