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.

purposeGivastomig 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

methodsA 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.

resultsNo 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%.

conclusionsGivastomig 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. See related commentary by Pretelli and Garralda, p. 4866.