一项阿维鲁单抗联合伊武单抗、乌托单抗及放射治疗晚期胃肠道恶性肿瘤患者的I/II期试验。
A phase I/II trial of avelumab combinations with ivuxolimab, utomilumab, and radiation therapy in patients with advanced gastrointestinal malignancies.
作者信息
Ahmed Jibran, Knisely Anne, Torrado Carlos, Stephen Bettzy, Yang Yali, Song Juhee, Alshawa Anas, Zarifa Abdulrazzak, Jhingran Anuja, Koay Eugene J, Morris Van Karlyle, Javle Milind, Wolff Robert A, Meric-Bernstam Funda, Pant Shubham, Rodon Jordi, Naing Aung
机构信息
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, United States.
出版信息
Oncologist. 2025 Mar 10;30(3). doi: 10.1093/oncolo/oyaf032.
BACKGROUND
Checkpoint agonists utomilumab (4-1BB agonist) and ivuxolimab (OX40 agonist) enhance Teffector cell function. Preclinical studies suggest that combining these drugs with avelumab (anti-PD-L1 antibody) can potentially synergize this effect. In addition, tissue abscopal effects of radiation therapy may improve antigen presentation, complementing PD-L1 blockade. We conducted a single institution, open-label, multi-arm, non-randomized, phase 1/2 clinical trial of avelumab in combination with ivuxolimab, with or without utomilumab, and radiation therapy in patients with advanced solid tumors. Herein, we present a subgroup analysis in patients with gastrointestinal (GI) tumors (pancreatic, colon, gastric, and hepatocellular).
METHODS
The primary objectives of this study were to assess safety, tolerability, and dose-limiting toxicities. The secondary objectives were to evaluate efficacy including response rate, progression free survival (PFS), as determined by immune-related Response Criteria in Solid Tumors (irRECIST) and overall survival (OS).
RESULTS
Thirty-one patients with pancreatic (n = 21), colorectal (n = 8), hepatocellular (n = 1), and gastric (n = 1) cancers were included in this study. The most common treatment-related adverse events (TRAEs) were chills (13%), diarrhea (10%), colitis (10%), fatigue (6%), and fever (6%). There were 3 instances of grade 3 diarrhea and colitis (10%) without any other grade ≥ 3 TRAEs Among the 24 patients evaluable for response, 9 (37.5%) had immune-related stable disease (irSD) and 14 (58.3%) had immune-related progressive disease (irPD). One patient had clinical progression without radiological confirmation. The median PFS was 2 months. Median OS was 5.6 months.
CONCLUSION
Combining avelumab with co-stimulatory checkpoint agonists produces modest activity without added safety concerns in patients with advanced GI malignancies (ClinicalTrials.gov Identifier: NCT03217747).
背景
检查点激动剂utomilumab（4-1BB激动剂）和ivuxolimab（OX40激动剂）可增强效应T细胞功能。临床前研究表明，将这些药物与avelumab（抗PD-L1抗体）联合使用可能会产生协同效应。此外，放射治疗的组织远隔效应可能会改善抗原呈递，补充PD-L1阻断作用。我们开展了一项单机构、开放标签、多臂、非随机的1/2期临床试验，研究avelumab联合ivuxolimab（联合或不联合utomilumab）及放射治疗用于晚期实体瘤患者的疗效。在此，我们展示了对胃肠道（GI）肿瘤（胰腺、结肠、胃和肝细胞癌）患者的亚组分析结果。
方法
本研究的主要目的是评估安全性、耐受性和剂量限制性毒性。次要目的是评估疗效，包括根据实体瘤免疫相关反应标准（irRECIST）确定的缓解率、无进展生存期（PFS）和总生存期（OS）。
结果
本研究纳入了31例胰腺癌（n = 21）、结直肠癌（n = 8）、肝细胞癌（n = 1）和胃癌（n = 1）患者。最常见的治疗相关不良事件（TRAEs）为寒战（13%）、腹泻（10%）、结肠炎（10%）、疲劳（6%）和发热（6%）。有3例3级腹泻和结肠炎（10%），无任何其他≥3级TRAEs。在24例可评估缓解情况的患者中，9例（37.5%）有免疫相关稳定疾病（irSD），14例（58.3%）有免疫相关疾病进展（irPD）。1例患者有临床进展但无影像学确认。中位PFS为2个月。中位OS为5.6个月。
结论
在晚期胃肠道恶性肿瘤患者中，avelumab与共刺激检查点激动剂联合使用产生的活性有限，且未增加安全性问题（ClinicalTrials.gov标识符：NCT03217747）。
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