2. Academic Validation
  3. 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

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

  • Clin Cancer Res. 2025 Jun 30:10.1158/1078-0432.CCR-24-4280. doi: 10.1158/1078-0432.CCR-24-4280.
Geoffrey Ku 1,  Lin Shen 2,  Farshid Dayyani 3,  Jeremy Kratz 4,  Xinjun Liang 5,  Funan Liu 6,  Zhenning Wang 7,  Laura Feller 8,  Eugenia Girda 9,  Hongming Pan 10,  Sunnie Kim 11,  Yanhong Deng 12,  Ting Deng 13,  Tianshu Liu 14,  John Powderly 15,  Kristen Spencer 16,  Reva Schneider 17,  Jordan Berlin 18,  Claire Cong Xu 19,  Christoph M Ahlers 20,  Xuejun Liu 21,  Jou-Ku Chung 19,  Peter Sabbatini 22,  Jinyoung Park 23,  Yangmi Lim 24,  Juyeun Jeon 23,  Yuan Meng 25,  Samuel J Klempner 26
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 2 Peking University Cancer Hospital, Beijing, China.
  • 3 University of California, Irvine, Orange, CA, United States.
  • 4 University of Wisconsin-Madison, Madison, United States.
  • 5 Hubei Cancer Hospital, Wuhan, China.
  • 6 The First Hospital of China Medical University, shenyang, liaoning, China.
  • 7 The First Hospital of China Medical University, China.
  • 8 HorizonBioAdvance, United States.
  • 9 Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States.
  • 10 Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 11 University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
  • 12 The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 13 Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 14 Zhongshan Hospital,Fudan University, Shanghai, China.
  • 15 Carolina BioOncology Institute, Huntersville, NC, United States.
  • 16 Perlmutter Cancer Center at New York University School of Medicine, New York, New York, United States.
  • 17 Mary Crowley Cancer Research - Medical City Dallas, Dallas, United States.
  • 18 Vanderbilt University Medical Center, Nashville, TN, United States.
  • 19 I-Mab Biopharma, United States.
  • 20 I-Mab Biopharma, Rockville, Maryland, United States.
  • 21 I-MAB Biopharma, Rockville, MD, United States.
  • 22 I-MAB Biopharma, United States.
  • 23 ABL Bio, Korea (South), Republic of.
  • 24 ABL Bio, Seoul, Korea (South), Republic of.
  • 25 TJ Bio, China.
  • 26 Massachusetts General Hospital, Boston, MA, United States.
PMID: 40586719 DOI: 10.1158/1078-0432.CCR-24-4280
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 (PK), pharmacodynamics (PD), and antitumor activity of givastomig in advanced solid tumors.

Patients and methods: 75 patients were enrolled. Escalating givastomig doses of 0.1-18 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 gastroesophageal carcinoma (GEC) were treated with 5-15 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 (ORR) 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.

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