PMID- 33610734 OWN - NLM STAT- MEDLINE DCOM- 20210421 LR - 20210421 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 32 IP - 5 DP - 2021 May TI - FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. PG - 609-619 LID - S0923-7534(21)00122-8 [pii] LID - 10.1016/j.annonc.2021.02.005 [doi] AB - 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/m(2) then 600 mg/m(2) Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m(2) 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/m(2) 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. CI - Copyright (c) 2021. Published by Elsevier Ltd. FAU - Sahin, U AU - Sahin U AD - 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. FAU - Tureci, O AU - Tureci O AD - Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH. FAU - Manikhas, G AU - Manikhas G AD - Department of Oncology, City Clinical Oncology Center, St. Petersburg, Russia. FAU - Lordick, F AU - Lordick F AD - Department of Medicine II and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany. FAU - Rusyn, A AU - Rusyn A AD - Department of Oncology, Transcarpathian Regional Clinical Oncological Center, Uzhhorod, Ukraine. FAU - Vynnychenko, I AU - Vynnychenko I AD - Sumy State University, Sumy Regional Clinical Oncology Center, Oncothoracic Department, Sumy, Ukraine. FAU - Dudov, A AU - Dudov A AD - Department of Oncology, Acibadem City Clinic Mladost, Sofia, Bulgaria. FAU - Bazin, I AU - Bazin I AD - Department of Clinical Pharmacology and Chemotherapy, Russian Oncology Research Center n. a. N.N. Blokhin, Moscow, Russia. FAU - Bondarenko, I AU - Bondarenko I AD - Dnipropetrovsk Medical Academy, City Multispecialty Clinical Hospital #4, Department of Chemotherapy, Dnipropetrovsk, Ukraine. FAU - Melichar, B AU - Melichar B AD - Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. FAU - Dhaene, K AU - Dhaene K AD - MD Dhaene Pathology Lab BVBA, Destelbergen, Belgium. FAU - Wiechen, K AU - Wiechen K AD - Department of Pathology, Klinikum Worms GmbH, Institute for Pathology, Worms, Germany. FAU - Huber, C AU - Huber C AD - 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. FAU - Maurus, D AU - Maurus D AD - Formerly of Ganymed Pharmaceuticals GmbH, Mainz, Germany. FAU - Arozullah, A AU - Arozullah A AD - Astellas Pharma Global Development, Inc., Northbrook, USA. FAU - Park, J W AU - Park JW AD - Astellas Pharma Global Development, Inc., Northbrook, USA. FAU - Schuler, M AU - Schuler M AD - West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. FAU - Al-Batran, S-E AU - Al-Batran SE AD - Institute of Clinical Cancer Research (IKF) at Krankenhaus Nordwest, Frankfurt, Germany. Electronic address: albatran.salah@khnw.de. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210219 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Antibodies, Monoclonal) RN - 0 (CLDN18 protein, human) RN - 0 (Claudins) RN - 6804DJ8Z9U (Capecitabine) RN - TF5MPQ8WGY (zolbetuximab) SB - IM CIN - Ann Oncol. 2021 May;32(5):584-586. PMID: 33677015 MH - *Adenocarcinoma/drug therapy MH - Adolescent MH - Adult MH - Antibodies, Monoclonal/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Capecitabine/therapeutic use MH - Claudins/genetics/therapeutic use MH - *Esophageal Neoplasms/drug therapy MH - Esophagogastric Junction MH - Humans MH - *Stomach Neoplasms/drug therapy OTO - NOTNLM OT - advanced gastric cancer OT - advanced gastroesophageal junction adenocarcinoma OT - advanced oesophageal adenocarcinoma OT - capecitabine (EOX) OT - claudin 18.2 OT - epirubicin OT - oxaliplatin OT - zolbetuximab COIS- Disclosure US reports co-founder and shareholder at Ganymed and also holds several patents, with royalties paid by Astellas; founder, chief executive officer, and shareholder of BioNTech. OT reports founder and chief executive officer of Ganymed until the end of 2016; currently an employee and chief medical officer of BioNTech; patents for the investigational agent, zolbetuximab, with royalties paid by Astellas; consultancy fees from Astellas Pharma. FL reports personal fees and/or grants from Astellas, AstraZeneca, Bristol-Myers Squibb (BMS), BioNTech, Lilly, Elsevier, Infomedica, Merck, Merck Sharp & Dohme (MSD), Roche, Servier, and Amgen. BM reports honoraria from Angelini Pharma, Astellas, Bayer, BMS, Eliamm, Merck Serono, MSD, Novartis, Pfizer, Roche, and Sanofi. KW reports honoraria from Ganymed Pharmaceuticals. CH reports being a co-founder, supervisory board member, and shareholder of Ganymed Pharmaceuticals. Additionally, being a co-founder, supervisory board member, and shareholder of BioNTech SE, co-founder, advisor and former supervisory board member of TRON, board member to the cutting-edge technology cluster CI3, and president of the international cancer immunotherapy network CIMT. AA and JP report employment from Astellas. MS reports consultant fees from AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche, and Takeda; honoraria from Abbvie, Boehringer Ingelheim, BMS, MSD, Novartis, and Pierre Fabre; research funding from AstraZeneca, Boehringer Ingelheim, BMS, and Novartis, and patents with the University Duisburg-Essen. S-EA reports advisory role from Merck, Roche, Celgene, Lilly, Nordic Pharma, BMS, MSD; speaker role from Roche, Celgene, Lilly, Nordic Pharma, AIO gGmbH, MCI, Promedicis, Forum fur Medizinische Fortbildung; CEO/founder of IKF Klinische Krebsforschung GmbH; and clinical trial fees from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly, German Cancer Aid (Krebshilfe), and German Research Foundation; and translational research from the Federal Ministry of Education and Research. All other authors have declared no conflicts of interest. Data sharing Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx. EDAT- 2021/02/22 06:00 MHDA- 2021/04/22 06:00 CRDT- 2021/02/21 20:30 PHST- 2020/08/24 00:00 [received] PHST- 2021/01/29 00:00 [revised] PHST- 2021/02/03 00:00 [accepted] PHST- 2021/02/22 06:00 [pubmed] PHST- 2021/04/22 06:00 [medline] PHST- 2021/02/21 20:30 [entrez] AID - S0923-7534(21)00122-8 [pii] AID - 10.1016/j.annonc.2021.02.005 [doi] PST - ppublish SO - Ann Oncol. 2021 May;32(5):609-619. doi: 10.1016/j.annonc.2021.02.005. Epub 2021 Feb 19.