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
  • 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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