A multicentre, phase 2a study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study
Mené sur 54 patients atteints d'un adénocarcinome de l'estomac, de la jonction œsogastrique ou de l'œsophage réfractaire ou récidivant et surexprimant CLDN18.2, cet essai de phase IIa évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du zolbétuximab (un anticorps ciblant CLDN18.2) dispensé en monothérapie
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 1, 300 mg/m2; Cohort 2, 600 mg/m2); additional patients were enrolled into a dose-expansion cohort (Cohort 3, 600 mg/m2). The primary endpoint was the objective response rate (ORR: complete and partial response); secondary endpoints included clinical benefit (ORR + stable disease), 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 five infusions. Antitumour activity data were available for 43 patients, of whom four achieved partial response (ORR 9%) and six (14%) had stable disease 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