Impact of the tumor immune contexture in microsatellite-stable metastatic colorectal cancer treated with avelumab, cetuximab, and irinotecan
The treatment of patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) remains a significant clinical challenge. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), induces immunogenic cell death, potentially synergizing with immune checkpoint inhibitors. The phase 2, proof-of-concept, single-arm AVETUXIRI trial (ClinicalTrials.gov: NCT03608046) evaluates the safety and efficacy of cetuximab, irinotecan (a topoisomerase I inhibitor), and avelumab (an anti-programmed cell death ligand 1 [PD-L1]) in 57 patients with RAS wild-type or mutated MSS mCRC refractory to chemotherapy and anti-EGFR mAbs. Exploratory objectives include investigating the tumor immune microenvironment within mCRC biopsies performed during the trial and correlating it with treatment activity. A manageable safety profile is observed. Although the overall efficacy endpoints are not met, biomarkers associated with clinical efficacy are identified. Patients exhibiting a high Immunoscore, strong cytotoxic and T cell proximity to tumor cells, and a high genetic immunoediting score within mCRC biopsies before treatment demonstrate significant therapeutic survival benefit, independent of RAS tumor mutation status.
Authors
- Elena Benidovskaya (ORCID: https://orcid.org/0000-0003-3646-9268)
- Aline van Maanen (ORCID: https://orcid.org/0000-0001-5952-726X)
- Marc Van den Eynde (ORCID: https://orcid.org/0000-0002-1405-4785)
- Fazulur Rehaman Vempalli (ORCID: https://orcid.org/0000-0001-7715-3185)
- Pierre Goffette (ORCID: https://orcid.org/0000-0001-8525-5499)
- Wouter Hendrickx (ORCID: https://orcid.org/0000-0002-7649-5092)
- Caroline Bouzin (ORCID: https://orcid.org/0000-0003-0694-1947)
- Marie-Laure Castella
- Javier Carrasco (ORCID: https://orcid.org/0000-0001-6436-0863)
- Raphaël Helaers (ORCID: https://orcid.org/0000-0002-7046-7867)
- Astrid De Cuyper
- Nicolas van Baren (ORCID: https://orcid.org/0000-0003-4548-0266)
- Simon P. Beyaert (ORCID: https://orcid.org/0000-0002-7241-526X)
- Isabelle Sinapi
- Luigi Ferraro (ORCID: https://orcid.org/0000-0003-2860-6568)
- Nicolas D. Huyghe (ORCID: https://orcid.org/0000-0002-9234-6388)
- Jérôme Galon (ORCID: https://orcid.org/0000-0001-9635-1339)
- Davide Bedognetti (ORCID: https://orcid.org/0000-0002-5857-773X)
- Michele Ceccarelli (ORCID: https://orcid.org/0000-0002-4702-6617)
- Tariq Masoodi (ORCID: https://orcid.org/0000-0002-9186-6349)
- Benoît Ghaye (ORCID: https://orcid.org/0000-0002-3239-9672)
- Finoula Maestre Osorio
Institutions
- Qatar Airways (Qatar) (QA)
- Cliniques Universitaires Saint-Luc (BE)
- Inserm (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Centre de Recherche des Cordeliers (FR)
- de Duve Institute (BE)
- European Society for Therapeutic Radiology and Oncology (BE)
- Hamad bin Khalifa University (QA)
- Grand Charleroi Hospital (BE)
- Sylvester Comprehensive Cancer Center (US)
- UCLouvain (BE)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102201
- Citations
- 3
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Sidra Medicine
- Fonds De La Recherche Scientifique - FNRS