A phase 1/2 study of LM-302, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate in patients with advanced gastric/gastroesophageal junction cancer.
Chunmei Bai, Junli Xue, Yi Zheng, Meili Sun, Jieer Ying, Fuxiang Zhou, Yiyi Yu, Yuping Sun, Ligang Xing, Yanqiao Zhang, Jinhua Wen, Jianping Xiong, Heshui Wu, Xiuli Yang, Lixin Wan, Shiwei Guo, Rusen Zhao, Zhizhen Zhu, Zhihua Gong, Jin Li
Abstract
3028 Background: LM-302 is a novel and potent MMAE antibody-drug conjugate (ADC) targeting CLDN18.2, which is highly expressed in gastric/gastroesophageal junction (GEJ), pancreatic, and biliary tract cancers. Preclinical studies of LM-302 have demonstrated compelling anti-tumor activity in multiple CLDN18.2-positive cell-lines and xenograft models. Methods: This phase 1/2 study included dose escalation phase and dose expansion phase. In the dose escalation phase, eligible patients received LM-302 once every three weeks (0.2-2.8 mg/kg Q3W), and once every two weeks (1.8-2.0 mg/kg Q2W) to evaluate the safety, tolerability, and pharmacokinetics. In the dose expansion phase, CLDN18.2-positive patients received LM-302 at recommended phase 2 doses of 2.4 mg/kg Q3W or 1.8 mg/kg Q2W to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs) in phase 1, and objective response rate (ORR) in phase 2. Here we report the results from safety analysis of LM-302 and efficacy data in gastric/GEJ cancer. Results: As of September 23, 2023, 135 patients received LM-302 treatment and the median prior lines of systemic therapy were 2 (range 1-4). In phase 1 and 2, most common TRAEs were white blood cell decreased (51.9%), neutrophil count decreased (51.1%), anaemia (38.5%), vomiting (36.3%), and nausea (34.1%). The most frequent grade ≥3 TRAEs were neutrophil count decreased (22.2%) and white blood cell decreased (17.8%). In phase 2 dose expansion, 52 CLDN18.2-positive (TC ≥ 50%, IHC ≥ 2+) gastric/GEJ cancer patients were enrolled (4 pts at 2.4mg/kg Q3W, 48 pts at 1.8mg/kg Q2W). 1.8mg/kg Q2W was selected for further evaluation based on PK, safety, and efficacy data analysis. Of 36 evaluable gastric/GEJ cancer patients who received at least two or more prior therapies, 11 partial response (PR) and 16 stable disease (SD) were observed. The ORR was 30.6% (11/36), and DCR was 75.0% (27/36). The median PFS was 7.16 months (95% CI 2.72-NA). The median overall survival (OS) was not reached, with an OS rate of 95.0% at the 6-month (as of November 15, 2023). Conclusions: LM-302 was well-tolerated with a manageable safety profile and demonstrated promising anti-tumor activity in CLDN18.2-positive patients with third-line and beyond gastric/GEJ cancer. The results support further investigation of LM-302 as a new therapeutic approach to treat CLDN18.2-positive gastric/GEJ cancer. Clinical trial information: NCT05161390 .