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

作者：Jia Liu, Jianwei Yang, Yuping Sun, Jifang Gong, Jinbo Yue, Yueyin Pan, Meili Sun, Rongfeng Song, Xiuying Xiao, Andrea Tazbirkova, Jian Ruan, Zhenyang Liu, Zimin Liu, Zhi‐Hua Li, Lili Sheng, Yanru Qin, Jieer Ying, Xianjun Yu, Jian Zhang, Yiping Mou, Chuangxin Lu, Ping Chen, Suyi Li, Jie Li, Xiujuan Qu, Ting Deng, Juan Du, Aiping Zhou, Enxiao Li, Xianglin Yuan, Xinjun Liang, Weiming Yu, Michelle Frances Morris, Yang Luo, Xin Zhao, Yingmei Guo, Hui Zhou, Lin Shen · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-03783-8 · 被引用次数：39 · 研究领域：Gastric Cancer Management and Outcomes、Gastrointestinal Tumor Research and Treatment、Colorectal Cancer Treatments and Studies

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−1, 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−1 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 opt...