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Cited by 256Cancer Immunotherapy and BiomarkersColorectal Cancer Treatments and StudiesGenetic factors in colorectal cancer

Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): A randomised, open-label, phase 3 trial

André, Thierry, Elez, Elena, Lenz, Heinz-Josef, Jensen, Lars Henrik, Touchefeu, Yann, Van Cutsem, Eric, Garcia-Carbonero, Rocio, Tougeron, David +21 more·2025·The Lancet
DOI 10.1016/s0140-6736(24)02848-4
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Abstract

Background CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines.Methods CheckMate 8HW is a randomised, open-label, international, phase 3 trial at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adults with unresectable or metastatic colorectal cancer across different lines of therapy and microsatellite instability-high or mismatch repair-deficient status per local testing were randomly assigned (2:2:1) to nivolumab plus ipilimumab (nivolumab 240 mg, ipilimumab 1 mg/kg, every 3 weeks for four doses; then nivolumab 480 mg every 4 weeks; all intravenously), nivolumab (240 mg every 2 weeks for six doses, then 480 mg every 4 weeks; all intravenously), or chemotherapy with or without targeted therapies. The dual independent primary endpoints were progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus chemotherapy (first line) and progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. This study is registered with ClinicalTrials.gov (NCT04008030).Findings Between Aug 16, 2019, and April 10, 2023, 707 patients were randomly assigned to nivolumab plus ipilimumab (n=354) or nivolumab alone (n=353). 296 (84%) of 354 patients in the nivolumab plus ipilimumab group and 286 (81%) of 353 patients in the nivolumab group were centrally confirmed to have microsatellite instability-high or mismatch repair-deficient status. At the data cutoff on Aug 28, 2024, median follow-up (from randomisation to data cutoff) was 47·0 months (IQR 38·4 to 53·2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio 0·62, 95% CI 0·48-0·81; p=0·0003). Median progression-free survival was not reached with nivolumab plus ipilimumab (95% CI 53·8 to not estimable) and was 39·3 months with nivolumab (22·1 to not estimable). Treatment-related adverse events of any grade occurred in 285 (81%) of 352 patients receiving nivolumab plus ipilimumab and in 249 (71%) of 351 patients receiving nivolumab; grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) patients, respectively. There were three treatment-related deaths: one event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and one pneumonitis event in the nivolumab group.Interpretation Nivolumab plus ipilimumab showed superior progression-free survival versus nivolumab across all treatment lines, with a manageable safety profile, in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These results, together with the first-line results of superior progression-free survival with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.Funding Bristol Myers Squibb and Ono Pharmaceutical.

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  • The Checkmate 8HW phase 3 study established the routine practice of the nivolumab-ipilimumab combination.

    “The recently published Checkmate 8HW phase 3 study established the routine practice of the nivolumab–ipilimimumab combination [87,88].”

    From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [87]

  • A relevant proportion of patients with metastatic dMMR/MSI-H CRC still do not respond to ICB, with tumour progression within the first 6 months: up to 50% in single-agent ICB and up to 25% in double-agent ICB.

    “careful analysis of clinical trials shows that a relevant proportion of patients with metastatic dMMR/MSI-H CRC still do not respond to immune checkpoint blockade101 107 with tumour progression within the first 6 months (up to 50% and up to 25% in single and double agent ICB therapy, respectively)”

    From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [107]

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Authors
André, T., Elez, E., Lenz, H.-J., Jensen, L. H., Touchefeu, Y., Van Cutsem, E., Garcia-Carbonero, R., Tougeron, D., Mendez, G. A., Schenker, M., de la Fouchardiere, C., Limon, M. L., Yoshino, T., Li, J., Manzano Mozo, J. L., Dahan, L., Tortora, G., Chalabi, M., Goekkurt, E., Braghiroli, M. I., Joshi, R., Cil, T., Aubin, F., Cela, E., Chen, T., Lei, M., Jin, L., Blum, S. I., & Lonardi, S.
Affiliations
  • Sorbonne Université (FR)
  • USC Norris Comprehensive Cancer Center (US)
  • Vejle Sygehus (DK)
  • Centre Hospitalier Universitaire de Nantes (FR)
  • Centre Hospitalier Universitaire de Poitiers (FR)
  • Fundacion Favaloro Hospital Universitario (AR)
  • University of Medicine and Pharmacy of Craiova (RO)
  • National Cancer Center Hospital East (JP)
  • Shanghai East Hospital (CN)
  • Agostino Gemelli University Polyclinic (IT)
  • The Netherlands Cancer Institute (NL)
  • University Cancer Center Hamburg (DE)
  • Universidade de São Paulo (BR)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Bristol-Myers Squibb (United States) (US)
  • Istituto Oncologico Veneto (IT)
Corresponding author
André, Thierry
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2025-02
Volume
405
Issue
10476
Pages
383-395
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(24)02848-4
OpenAlex
W4406818361
Cited by
256
References
22
Citations by year
2026: 155 · 2025: 101
FWCI
106.01
Type
journal article
Language
en
Update notices
erratum (2025-03-01)
Open access
closed
Licence
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
Funders
  • Ono Pharmaceutical Co Ltd
  • Bristol-Myers Squibb Company
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
metastatic colorectal cancer, microsatellite instability-high, mismatch repair deficiency, nivolumab, ipilimumab, immune checkpoint inhibitors, combination immunotherapy, progression-free survival, first-line therapy, chemotherapy, treatment lines, interim analysis, predictive biomarkers, PD-L1 expression, tumor-infiltrating lymphocytes, tumor mutational burden, PD-1/PD-L1 blockade
MeSH terms
Antineoplastic Agents, Immunological, Ipilimumab, Nivolumab, Progression-Free Survival, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Middle Aged, Colorectal Neoplasms, Microsatellite Instability, DNA Mismatch Repair

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