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

O Türeci, U Sahin, H Schulze-Bergkamen, Z Zvirbule, F Lordick, D Koeberle, P Thuss-Patience, T Ettrich, D Arnold, F Bassermann, S E Al-Batran, K Wiechen, K Dhaene, D Maurus, M Gold, C Huber, A Krivoshik, A Arozullah, J W Park, M Schuler, O Türeci, U Sahin, H Schulze-Bergkamen, Z Zvirbule, F Lordick, D Koeberle, P Thuss-Patience, T Ettrich, D Arnold, F Bassermann, S E Al-Batran, K Wiechen, K Dhaene, D Maurus, M Gold, C Huber, A Krivoshik, A Arozullah, J W Park, M Schuler

Abstract

Background: 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 and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CLDN18.2; IMAB362; gastric cancer; gastro-oesophageal junction adenocarcinoma; zolbetuximab.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Patient’s disposition. *Three patients from cohort 1 and 40 patients from cohorts 2+3 were included in the full analysis set, which was defined as the set of patients who received at least one dose of medication and for whom any efficacy data were available.
Figure 2.
Figure 2.
Duration of treatment and response with zolbetuximab. Duration of response for each individual patient. One patient had a prolonged response and received >70 infusions.
Figure 3.
Figure 3.
Best percentage change from baseline in tumour size with zolbetuximab in patients with gastric, GEJ, and oesophageal adenocarcinomas. Tumour diameter changes from baseline for each individual patient with (A)

Figure 4.

Treatment-emergent nausea and vomiting during…

Figure 4.

Treatment-emergent nausea and vomiting during treatment with zolbetuximab: (A) nausea and vomiting by…

Figure 4.
Treatment-emergent nausea and vomiting during treatment with zolbetuximab: (A) nausea and vomiting by gastrectomy status; (B) nausea by treatment cycle, first five doses of zolbetuximab; (C) vomiting by treatment cycle, first five doses of zolbetuximab. Patients were scheduled to receive i.v. infusions of zolbetuximab every 2 weeks for up to five infusions before potentially qualifying for continued treatment; nausea (B) and vomiting (C) events that occurred during continued treatment are not shown in this figure.
Figure 4.
Figure 4.
Treatment-emergent nausea and vomiting during treatment with zolbetuximab: (A) nausea and vomiting by gastrectomy status; (B) nausea by treatment cycle, first five doses of zolbetuximab; (C) vomiting by treatment cycle, first five doses of zolbetuximab. Patients were scheduled to receive i.v. infusions of zolbetuximab every 2 weeks for up to five infusions before potentially qualifying for continued treatment; nausea (B) and vomiting (C) events that occurred during continued treatment are not shown in this figure.

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Source: PubMed

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