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

Abstract 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 demonstrated manageable safety, dose-proportional exposure, and antitumor activity in patients with advanced solid tumors, particularly in CLDN18.2-positive GEC. A givastomig dose range of 5 to 12 mg/kg was chosen to combine with nivolumab and chemotherapy in part 2 of the study in frontline metastatic GEC.