Ci3 - Cluster of Individualized Immune Intervention, Mainz.
TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz.
Ann Oncol. 2019 Sep 1;30(9):1487-1495. doi: 10.1093/annonc/mdz199.
Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells.
Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile.
From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent.
Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials.
CLINICALTRIALS.GOV NUMBER: NCT01197885.
Claudin 18.2 (CLDN18.2) 在生理上局限于胃黏膜紧密连接；然而，在恶性转化时，细胞极性的紊乱导致 CLDN18.2 表位暴露在癌细胞表面。首个单抗药物，zolbetuximab（前称 IMAB362），与 CLDN18.2 结合，并能诱导 CLDN18.2 阳性细胞的免疫介导裂解。
患有晚期胃、胃食管交界处（GEJ）或食管腺癌，肿瘤细胞中 CLDN18.2 表达≥50%的患者，每 2 周静脉给予 zolbetuximab，计划给予 5 个疗程。至少有 3 名患者被纳入两个连续队列（队列 1300mg/m2；队列 2600mg/m2）；另外的患者被纳入剂量扩展队列（队列 3600mg/m2）。主要终点是客观缓解率（ORR：完全和部分缓解（PR））；次要终点包括临床获益（ORR+疾病稳定（SD））、无进展生存期、安全性/耐受性和 zolbetuximab 药代动力学特征。
从 2010 年 9 月至 2012 年 9 月，共纳入 54 例患者（队列 1，n=4；队列 2，n=6；队列 3，n=44）。队列 1 和 2 中有 3 名患者和队列 2/3 中有 25 名患者接受了至少 5 个疗程。43 例患者有抗肿瘤活性数据，其中 4 例患者获得 PR（ORR 9%），6 例（14%）患者 SD，临床获益率为 23%。在 CLDN18.2 表达≥70%的肿瘤细胞的亚组患者中，ORR 为 14%（n=29）。81.5%（n=54）的患者出现与治疗相关的不良事件；最常见的是恶心（61%）、呕吐（50%）和疲劳（22%）。
zolbetuximab 单药治疗在 CLDN18.2 阳性的晚期胃或 GEJ 腺癌患者中具有良好的耐受性和抗肿瘤活性，其缓解率与胃/GEJ 癌试验中单药靶向药物报道的缓解率相似。
临床试验.gov 编号：NCT01197885。
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