CLDN18.2–targeting antibody–drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial
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
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−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 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 . In this multicenter phase 1 trial, treatment with IBI343, a CLDN18.2-targeting antibody–drug conjugate, was safe and showed encouraging clinical responses in patients with advanced gastric or gastroesophageal junction adenocarcinoma.