A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer.
Rui‐Hua Xu, Dan‐Yun Ruan, Dong‐Sheng Zhang, Furong Liu, Suxia Luo, Zhixiang Zhuang, Zhen-Ning Wang, Funan Liu, Yanqiao Zhang, Jianwei Yang, Zhendong Chen, Yongsheng Wang, Junye Wang, Xiaohua Liang, Xiaojie Wu, Yulong Zheng, Jian Liu, Xi Shi, Wei Liu, Bo Chen
Abstract
434420 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced gastric/gastroesophageal junction (G/GEJ) cancer. CMG901, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E (MMAE), has demonstrated potent anti-tumor activity in preclinical studies. Methods: This phase 1 trial included a dose-escalation phase (part A; 0.3-3.4 mg/kg) and a dose-expansion phase (part B; 2.2, 2.6, and 3.0 mg/kg) to evaluate safety, tolerability, and anti-tumor activity of CMG901 in patients (pts) with advanced G/GEJ cancer and other solid tumors. CLDN18.2 expression was not required for study entry in part A, but CLDN18.2 expression of ≥2+ membrane staining intensity in ≥5% tumor cells was required for G/GEJ cancer in part B. CMG901 was administrated intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety/tolerability and maximum tolerated dose (MTD) for part A, and objective response rate (ORR, per RECIST v1.1) and recommended phase 2 dose in part B. Here we present the G/GEJ cancer data from this ongoing trial. Results: MTD was not reached during dose escalation. As of July 24, 2023, 113 G/GEJ cancer pts received CMG901 at doses of 2.2-3.0 mg/kg (6 pts from part A and 107 pts from part B). The median prior lines of systemic therapy were 2 (range 1-6). Most common TEAEs were anaemia (62.8%), vomiting (57.5%), and hypoalbuminaemia (57.5%). Neutrophil count decreased (18.6%) and anaemia (13.3%) were the most frequent grade ≥3 TEAEs. Of 89 evaluable (≥1 post-treatment scan) CLDN18.2-positive pts, confirmed ORR was 32.6% (Table). For all 93 CLDN18.2-positive pts, the median progression-free survival was 4.76 months (95%CI 3.35-6.14) after a median follow-up of 5.98 months. The median overall survival (OS) was not reached, with an OS rate of 56.4% at 9 months. Conclusions: CMG901 demonstrated promising clinical efficacy in CLDN18.2-positive G/GEJ cancer pts, with a manageable safety profile. These results support further evaluation of CMG901 in CLDN18.2-positive G/GEJ cancer. Clinical trial information: NCT04805307 .[Table: see text]