BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Astellas Pharma Global Development Inc Northbrook USA

Biopharmaceutical New Technologies Corporation Mainz Germany; CI3 Cluster of Individualized Immune Intervention Mainz Germany; formerly of Ganymed Pharmaceuticals GmbH

Department of Clinical Pharmacology and Chemotherapy Russian Oncology Research Center n a N N Blokhin Moscow Russia

Department of Experimental and Translational Oncology TRON Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany; Biopharmaceutical New Technologies Corporation Mainz Germany; CI3 Cluster of Individualized Immune Intervention Mainz Germany; formerly of Ganymed Pharmaceuticals GmbH

Department of Experimental and Translational Oncology TRON Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany; Department of Oncology University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany; Biopharmaceutical New Technologies Corporation Mainz Germany

Department of Medicine 2 and University Cancer Center Leipzig University of Leipzig Medical Center Leipzig Germany

Department of Oncology Acibadem City Clinic Mladost Sofia Bulgaria

Department of Oncology City Clinical Oncology Center St Petersburg Russia

Department of Oncology Palacky University Medical School and Teaching Hospital Olomouc Czech Republic

Department of Oncology Transcarpathian Regional Clinical Oncological Center Uzhhorod Ukraine

Department of Pathology Klinikum Worms GmbH Institute for Pathology Worms Germany

Dnipropetrovsk Medical Academy City Multispecialty Clinical Hospital 4 Department of Chemotherapy Dnipropetrovsk Ukraine

Formerly of Ganymed Pharmaceuticals GmbH Mainz Germany

Institute of Clinical Cancer Research at Krankenhaus Nordwest Frankfurt Germany

MD Dhaene Pathology Lab BVBA Destelbergen Belgium

Sumy State University Sumy Regional Clinical Oncology Center Oncothoracic Department Sumy Ukraine

West German Cancer Center University Duisburg Essen and German Cancer Consortium Partner Site University Hospital Essen Essen Germany

Ann Oncol. 2021 May;32(5):584-586. doi: 10.1016/j.annonc.2021.02.021. PubMed

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Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives