CLDN18.2–targeting antibody–drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial

Aberrant expression of claudin18.2 (CLDN18.2) has frequently been observed in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, making it a promising therapeutic target for this aggressive cancer. While a monoclonal antibody targeting CLDN18.2 has been approved for G/GEJ adenocarcinoma, antibody-drug conjugates (ADCs) have also emerged as therapeutic modalities. IBI343 is an ADC consisting of a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to exatecan via site-specific glycol conjugation and a cleavable linker with a drug-to-antibody ratio of 4. Here we present the results from a phase 1 dose escalation and dose expansion study of the IBI343 ADC. A total of 127 patients were enrolled and dosed (19 in the escalation phase and 108 in the expansion phase). Dose-limiting toxicities occurred in two of six participants at a dose of 10 mg kg<sup>-1</sup>, including one with myelosuppression (grade 4) and one with both neutropenia (grade 4) and febrile neutropenia (grade 3). Minimal gastrointestinal adverse events (grade ≥3) were observed and no interstitial lung disease was reported. The recommended phase 2 dose of IBI343 was determined to be 6 mg kg<sup>-1</sup> every 3 weeks with a confirmed objective response rate of 29% and median progression-free survival of 5.5 months in CLDN18.2-high (2+/3+ ≥ 75%) G/GEJ adenocarcinoma. IBI343 was well tolerated, with a manageable safety profile and promising efficacy in G/GEJ adenocarcinoma. Further research is required to understand optimal sequencing, and biomarker-informed combination therapy, in G/GEJ tumors given the development of multiple therapies targeting CLDN18.2 in addition to human epidermal growth factor receptor 2 and programmed cell death 1 ligand 1.ClinicalTrials.gov registration: NCT05458219 .

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Publication Details

Journal
Nature Medicine
Published
2025-07-16
DOI
https://doi.org/10.1038/s41591-025-03783-8
Citations
19
Primary Topic
Gastric Cancer Management and Outcomes
Type
article
Field-Weighted Citation Impact
28.85

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article

CLDN18.2–targeting antibody–drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial

Michelle Frances Morris, Xiujuan Qu, Jinbo Yue, Aiping Zhou et al.
19 citations
Nature Medicine
Gastric Cancer Management and Outcomes
28.85
article

CLDN18.2–targeting antibody–drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial

Michelle Frances Morris, Xiujuan Qu, Jinbo Yue, Aiping Zhou, Andrea Tazbirkova, Zimin Liu, Hui Zhou, Yuping Sun, Juan Du, Xiuying Xiao, Yingmei Guo, Jian Ruan, Yang Luo, Weiming Yu, Yanru Qin, Yueyin Pan, Lin Shen, Chuangxin Lu, Meili Sun, Ping Chen, Zhi‐Hua Li, Xianjun Yu, Jia Liu, Jianwei Yang, Ting Deng, Xin Zhao, Xinjun Liang, Jian Zhang, Jie Li, Suyi Li, Xianglin Yuan, Enxiao Li, Lili Sheng, Zhenyang Liu, Jieer Ying, Jifang Gong, Rongfeng Song, Yiping Mou
article en
19 citations

Abstract

Aberrant expression of claudin18.2 (CLDN18.2) has frequently been observed in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, making it a promising therapeutic target for this aggressive cancer. While a monoclonal antibody targeting CLDN18.2 has been approved for G/GEJ adenocarcinoma, antibody-drug conjugates (ADCs) have also emerged as therapeutic modalities. IBI343 is an ADC consisting of a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to exatecan via site-specific glycol conjugation and a cleavable linker with a drug-to-antibody ratio of 4. Here we present the results from a phase 1 dose escalation and dose expansion study of the IBI343 ADC. A total of 127 patients were enrolled and dosed (19 in the escalation phase and 108 in the expansion phase). Dose-limiting toxicities occurred in two of six participants at a dose of 10 mg kg<sup>-1</sup>, including one with myelosuppression (grade 4) and one with both neutropenia (grade 4) and febrile neutropenia (grade 3). Minimal gastrointestinal adverse events (grade ≥3) were observed and no interstitial lung disease was reported. The recommended phase 2 dose of IBI343 was determined to be 6 mg kg<sup>-1</sup> every 3 weeks with a confirmed objective response rate of 29% and median progression-free survival of 5.5 months in CLDN18.2-high (2+/3+ ≥ 75%) G/GEJ adenocarcinoma. IBI343 was well tolerated, with a manageable safety profile and promising efficacy in G/GEJ adenocarcinoma. Further research is required to understand optimal sequencing, and biomarker-informed combination therapy, in G/GEJ tumors given the development of multiple therapies targeting CLDN18.2 in addition to human epidermal growth factor receptor 2 and programmed cell death 1 ligand 1.ClinicalTrials.gov registration: NCT05458219 .

Nature MedicineVol. 31(9)
Qingdao University (CN), Garvan Institute of Medical Research (AU), Sun Yat-sen University (CN), Shanghai Jiao Tong University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Renji Hospital (CN), Tianjin Medical University Cancer Institute and Hospital (CN), UNSW Sydney (AU), St Vincent's Hospital Sydney (AU), Fudan University Shanghai Cancer Center (CN), Peking University Cancer Hospital (CN), Jiangxi Provincial Cancer Hospital (CN), Sun Yat-sen Memorial Hospital (CN), Zhejiang Cancer Hospital (CN), Shandong Tumor Hospital (CN), Sunshine Coast University Hospital (AU), Jinan Central Hospital (CN), Nanjing Drum Tower Hospital (CN), Ningbo Medical Center Lihuili Hospital (CN), Hunan Cancer Hospital (CN), Affiliated Hospital of Qingdao University (CN), First Affiliated Hospital of Xi'an Jiaotong University (CN), Ningxia Medical University (CN), Anhui Provincial Hospital (CN), Zhejiang Provincial People's Hospital (CN), Canossa Private Hospital (AU), Henan Provincial People's Hospital (CN), Jining First People's Hospital (CN), Ningxia Medical University General Hospital (CN), Fujian Provincial Cancer Hospital (CN), The Kinghorn Cancer Centre (AU), First Affiliated Hospital of Zhengzhou University (CN), Tongji Hospital (CN), Hubei Cancer Hospital (CN), Shandong First Medical University (CN), First Affiliated Hospital Zhejiang University (CN), First Affiliated Hospital of Wannan Medical College (CN), Huazhong University of Science and Technology (CN), China Medical University (CN)
Innovent Biologics
Good health and well-being
Openalex Percentile: Top 0%
Gastric Cancer Management and Outcomes
28.85
DOIOpen Access PDFOpenAlex
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