U Sahin1, Ö Türeci2, G Manikhas3, F Lordick4, A Rusyn5, I Vynnychenko6, A Dudov7, I Bazin8, I Bondarenko9, B Melichar10, K Dhaene11, K Wiechen12, C Huber13, D Maurus14, A Arozullah15, J W Park15, M Schuler16, S-E Al-Batran17. 1. 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 (BioNTech) Corporation, Mainz, Germany. 2. Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH. 3. Department of Oncology, City Clinical Oncology Center, St. Petersburg, Russia. 4. Department of Medicine II and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany. 5. Department of Oncology, Transcarpathian Regional Clinical Oncological Center, Uzhhorod, Ukraine. 6. Sumy State University, Sumy Regional Clinical Oncology Center, Oncothoracic Department, Sumy, Ukraine. 7. Department of Oncology, Acibadem City Clinic Mladost, Sofia, Bulgaria. 8. Department of Clinical Pharmacology and Chemotherapy, Russian Oncology Research Center n. a. N.N. Blokhin, Moscow, Russia. 9. Dnipropetrovsk Medical Academy, City Multispecialty Clinical Hospital #4, Department of Chemotherapy, Dnipropetrovsk, Ukraine. 10. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. 11. MD Dhaene Pathology Lab BVBA, Destelbergen, Belgium. 12. Department of Pathology, Klinikum Worms GmbH, Institute for Pathology, Worms, Germany. 13. 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 (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH. 14. Formerly of Ganymed Pharmaceuticals GmbH, Mainz, Germany. 15. Astellas Pharma Global Development, Inc., Northbrook, USA. 16. West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 17. Institute of Clinical Cancer Research (IKF) at Krankenhaus Nordwest, Frankfurt, Germany. Electronic address: albatran.salah@khnw.de.
Abstract
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.
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 adenocarcinomapatients (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 adenocarcinomapatients 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.