A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

• Published in: Annals of oncology Vol. 30; no. 9; pp. 1487 - 1495
• Main Authors: Türeci, O., Sahin, U., Schulze-Bergkamen, H., Zvirbule, Z., Lordick, F., Koeberle, D., Thuss-Patience, P., Ettrich, T., Arnold, D., Bassermann, F., Al-Batran, S.E., Wiechen, K., Dhaene, K., Maurus, D., Gold, M., Huber, C., Krivoshik, A., Arozullah, A., Park, J.W., Schuler, M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2019; Oxford University Press
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - immunology; Adenocarcinoma - pathology; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; CLDN18.2; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - pathology; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - immunology; Esophageal Neoplasms - pathology; Esophagogastric Junction - drug effects; Esophagogastric Junction - pathology; Female; gastric cancer; gastro-oesophageal junction adenocarcinoma; Humans; IMAB362; Male; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Original; Stomach Neoplasms - drug therapy; Stomach Neoplasms - immunology; Stomach Neoplasms - pathology; Treatment Outcome; zolbetuximab; gastro-oesophageal junction adenocarcinoma; CLDN18.2; gastric cancer; IMAB362; zolbetuximab
• ISSN: 0923-7534; 1569-8041
• 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.
NCT01197885.