A First-in-Human Study of Givastomig, a CLDN18.2 and 4-1BB Bispecific Antibody, as Monotherapy in Patients with CLDN18.2-Positive Advanced or Metastatic Solid Tumors

作者：Geoffrey Y. Ku, Lin Shen, Farshid Dayyani, Jeremy D. Kratz, Xinjun Liang, Funan Liu, Zhenning Wang, Laura Feller, Eugenia Girda, Hongming Pan, Sunnie S. Kim, Yanhong Deng, Ting Deng, Tianshu Liu, John D. Powderly, Kristen Spencer, Reva Schneider, Jordan Berlin, Claire Xu, Christoph M. Ahlers, Xuejun Liu, Jou-Ku Chung, Peter Sabbatini, Jin-Young Park, Yangmi Lim, Juyeun Jeon, Yuan Meng, Samuel J. Klempner · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-24-4280 · 被引用次数：15 · 研究领域：Monoclonal and Polyclonal Antibodies Research、CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers

PURPOSE: Givastomig is a bispecific antibody that targets CLDN18.2 and conditionally activates local 4-1BB-expressing T cells. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of givastomig in advanced solid tumors. PATIENTS AND METHODS: A total of 75 patients were enrolled. Escalating givastomig doses of 0.1 to 18 mg/kg were evaluated in 36 patients with metastatic or advanced solid tumors. An additional 6 patients per cohort with CLDN18.2-positive (defined as membrane intensity score of ≥1+ on ≥1% of tumor cells) advanced or metastatic gastric cancer, gastroesophageal junction cancer, or gastroesophageal carcinoma (GEC) were treated with 5 to 15 mg/kg givastomig across four cohorts. Fifteen patients with CLDN18.2-positive GEC were then enrolled to the 12 mg/kg dose expansion cohort. RESULTS: No dose-limiting toxicities were reported up to 18 mg/kg, and a maximum tolerated dose was not reached. The most common treatment-related adverse events (in ≥10% of patients) were nausea, anemia, fatigue, white blood cell count decrease, vomiting, and increased alanine aminotransferase. Givastomig exposure increased dose proportionally, and soluble 4-1BB approached a plateau above 5 mg/kg. The 12 mg/kg dose was selected for dose expansion. A 16% objective response rate was observed in CLDN18.2-positive GEC above 5 mg/kg (N = 43). CLDN18.2 expression in responders ranged from 11% to 100%. CONCLUSIONS: Givastomig demo...