Huyghe Nicolas, Benidovskaya Elena, Masoodi Tariq, Sinapi Isabelle, De Cuyper Astrid, Vempalli Fazulur, Beyaert Simon, Bouzin Caroline, Osorio Finoula Maestre, Ferraro Luigi, van Baren Nicolas, Helaers Raphaël, Goffette Pierre, Ghaye Benoit, van Maanen Aline, Castella Marie-Laure, Ceccarelli Michele, Bedognetti Davide, Galon Jérôme, Hendrickx Wouter R L, Carrasco Javier, Van den Eynde Marc
IREC MIRO-ONCO, Laboratory of Oncology, UCLouvain, Brussels, Belgium.
Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Al-Rayyan, Qatar.
Cell Rep Med. 2025 Jul 15;6(7):102201. doi: 10.1016/j.xcrm.2025.102201. Epub 2025 Jun 24.
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.
微卫星稳定（MSS）转移性结直肠癌（mCRC）患者的治疗仍然是一项重大的临床挑战。西妥昔单抗是一种抗表皮生长因子受体（EGFR）单克隆抗体（mAb），可诱导免疫原性细胞死亡，可能与免疫检查点抑制剂产生协同作用。2期概念验证单臂AVETUXIRI试验（ClinicalTrials.gov：NCT03608046）评估了西妥昔单抗、伊立替康（一种拓扑异构酶I抑制剂）和阿维鲁单抗（一种抗程序性细胞死亡配体1 [PD-L1]）对57例对化疗和抗EGFR mAb难治的RAS野生型或突变型MSS mCRC患者的安全性和疗效。探索性目标包括研究试验期间进行的mCRC活检中的肿瘤免疫微环境，并将其与治疗活性相关联。观察到安全性可控。虽然未达到总体疗效终点，但确定了与临床疗效相关的生物标志物。在治疗前的mCRC活检中表现出高免疫评分、强烈的细胞毒性和T细胞与肿瘤细胞接近度以及高基因免疫编辑评分的患者显示出显著的治疗生存获益，与RAS肿瘤突变状态无关。
