Safety, tolerability, and preliminary efficacy results in patients with advanced gastric/gastroesophageal junction adenocarcinoma from a phase Ib/II study of CLDN18.2 CAR T-cell therapy (CT041).
Authors: QI Changsong , Liu Chang , Gong Jifang , Li Jian , Liu Dan , Ge Sai , Zhang Miao , Peng Zhi , Zhou Jun , Zhang Xiaotian , Zheng Ji , Xiao Jun , Yuan Daijing , Peng Yueying , Wang Huamao , Li Zonghai , Shen Lin 
Published: June 2022

4017 Background: Claudin18.2 (CLDN18.2) has emerged as a promising therapeutic target, which is normally confined to gastric mucosa tight junctions but is often expressed in gastric/gastroesophageal junction (G/GEJ) cancer. CT041, an CLDN18.2-redirected CAR T-cell therapy, showed promising anti-tumor activity in preclinical studies (Hua J. J Natl Cancer Inst. 2019). Recently reported results of a phase I study (Qi C. Ann. Oncol 2021) showed that CT041 was well tolerated and had encouraging efficacy in previously treated patients with CLDN18.2-positive advanced G/GEJ cancer. Here we report the preliminary safety and efficacy data on patients with G/GEJ cancer in an ongoing phase Ib/II study (CT041-ST-01, NCT04581473). Methods: This open-label, 2-part, multicenter, phase Ib/II study was conducted to assess the safety, tolerability and efficacy of CT041 in patients with previously treated, CLDN18.2-positive advanced G/GEJ cancer. The study consisted of a dose escalation/dose-expansion phase (phase Ib) and a safety/efficacy confirmatory phase (phase II). In the dose escalation/de-escalation phase, CT041 dose levels of 2.5 × 108 and 3.75 × 108 were investigated using 3 + 3 design. The primary objective of the phase Ib part was to determine the safety, tolerability and recommended phase 2 dose (RP2D) of CT041. Data are reported as of December 22, 2021. Results: From November 2020 to May 2021,14 eligible patients with G/GEJ cancer were enrolled in phase Ib. The median (range) age was 44.5 (23-71); 85.7% had received 2 prior lines of treatment and 14.3% had at least 3 lines; 57.1% had ≥ 3 metastatic organs, with 92.9% had peritoneal dissemination; 64.3% had signet ring cell carcinoma. Among them, 3 received 3.75 × 108 and 11 received 2.5 × 108 dose level with up to 3 doses, respectively. Most commonly reported AEs of grade 3 or higher were hematologic toxicity related with lymphodepletion. There were no dose-limiting toxicities, treatment-related death, neurologic toxicity (ICANS) or gastrointestinal toxicities observed. Most CRS were grade 1 or 2, and only one patient experienced grade 4 CRS and fully recovered. As of the data cut-off, 8 of 14 (57.1%) patients achieved partial response (PR); 2 of 14 (14.3%) patients showed stable disease (SD) . With a median follow-up time of 8.9 months (95%CI 5.91, NE), the median progression-free survival (PFS) was 5.6 months (95%CI 1.9, 7.4), and median overall survival (OS) was 10.8 months (95%CI 5.1, NE) with 7 patients still alive at last follow-up. Conclusions: These preliminary results suggest that CT041 had manageable safety/tolerability profile and promising efficacy in patients with previously treated advanced G/GEJ cancer. This study is ongoing with further investigation of CT041 in phase II underway. Clinical trial information: NCT04581473.