Journal Article

Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma

Kawazoe, Akihito, Nakanishi, Yuka, Hirakawa, Akihiro, Shitara, Kohei, Ueno, Yoko, Fukuda, Musashi, Raizer, Jeffrey, Arozullah, Ahsan, Furuki, Satomi

2023

Overview

Zolbetuximab is a chimeric monoclonal antibody that targets claudin‐18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin‐18.2–positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m2 on cycle 1, day 1 followed by 600 mg/m2 every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m2 Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose‐limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression‐free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug‐related treatment‐emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3–85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6–11.4) and median PFS was 2.6 months (0.9–2.8). In Arm B (n = 3), median OS was 6.4 months (2.9–6.8) and median PFS was 1.7 months (1.2–2.1). Zolbetuximab exhibited no new safety signals with limited single‐agent activity in Japanese patients. Here we show for the first time that zolbetuximab treatment does not lead to any new safety signals specifically in Japanese patients with advanced G/GEJ cancer; most (94.4%) patients experienced zolbetuximab‐related gastrointestinal adverse events, which were not severe (grade 1–2) and did not lead to study discontinuation or death. Zolbetuximab monotherapy exhibited limited anticancer efficacy in this study. The promising efficacy profile of zolbetuximab when combined with chemotherapy observed in phase 2 trials and the tolerable safety profile observed in this study suggest that zolbetuximab in combination with chemotherapy may be a suitable treatment specifically for Japanese patients with advanced G/GEJ cancer.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adenocarcinoma / Adenocarcinoma - pathology / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - pharmacokinetics / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Combined Chemotherapy Protocols / Biomarkers / Cancer therapies / Chemotherapy / Claudins / CLDN18.2 protein / clinical trial phase 1 / Cytotoxicity / Disease control / East Asian People / Esophageal Neoplasms - pathology / esophagogastric junction / Esophagogastric Junction - pathology / Gastric cancer / Growth factors / Humans / Immunogenicity / Metastases / Metastasis / Monoclonal antibodies / Original / ORIGINAL ARTICLES / Patients / Pharmacokinetics / Response rates / Safety / Stomach Neoplasms - pathology / Tumors / zolbetuximab