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.

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 .