FAST: An international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma
Salah-Eddin Al-Batran, Martin H. Schuler, Zanete Zvirbule, Georgiy Manikhas, Florian Lordick, Andriy Rusyn, Yuriy Vynnyk, Ihor Vynnychenko, Natalia Fadeeva, Marina Nechaeva, Assen Dudov, Evgeny Gotovkin, Alexander Pecheniy, Igor Bazin, Igor Bondarenko, Bohuslav Melichar, Christian Mueller, Christoph Huber, Oezlem Tureci and Ugur Sahin
Institute of Clinical Cancer Research, Nordwest Hospital, Frankfurt Am Main, Germany; Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany; Riga East University Hospital, LLC, Riga, Latvia; City Clinical Oncology Center, St. Petersburg, Russia; University Cancer Center Leizpig, University Medicine Leipzig, Leipzig, Germany; Zakarpattya Regional Clinical Oncological Center, Department of Chemotherapy, Uzhgorod, Ukraine; Kharkiv Regional Clinical Oncology Center, Abdominal Department, Kharkiv, Ukraine; Sumy Regional Clinical Oncology Center, Oncothoracic Department, Sumy State University, Sumy, Ukraine; Chelyabinsk Regional Clinical Oncology Center, Chelyabinsk, Russian Federation; Arkhangelsk Regional Clinical Oncologic Dispensary, Arkhangelsk, Russia; Multiprofile Hospital for Active Treatment “Tsaritsa Yoanna – ISUL”, Sofia, University Hospital City Clinic Oncology Center, Sofia, Bulgaria; Ivanovo Regional Oncology Dispensary, Ivanovo, Russia; Orel Oncology Center, Orel, Russian Federation; Russian Oncology Research Center n. a. N.N. Blokhin, Moscow, Russian Federation; Dnipropetrovsk Medical Academy, City Multispecialty Clinical Hospital #4, Department of Chemotherapy, Dnipropetrovsk, Ukraine; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Ganymed Pharmaceuticals AG, Mainz, Germany; TRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Abstract
LBA4001
Background: Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 Kit). Eligible pts had a CLDN18.2 expression of 
2+ in 40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). The study was extended by an exploratory Arm3 (N = 85) to investigate a high dose IMAB362 (1000 mg/m2) plus EOX, (not subject here). The primary study endpoint was PFS (Arm 1 v 2, 70% power, HR 0.72, 1-sided p = 0.1). Results: 730 pts were consented, of whom 352 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age, 58 yrs; male 64%; gastric, 80%; GEJ, 16%; esophageal, 4%) were randomized into Arms1 and 2. The study met its endpoints. IMAB362 plus EOX improved PFS (median 5.7 v 7.9 mon; HR 0.5; 95% CI 0.35–0.78, 1-sided p = 0.001) and OS (median 8.7 v 12.5 mon; HR 0.5, 95% CI 0.28–0.73) compared to EOX alone. In the subpopulation with very high CLDN18.2 expression ( 2+ intensity in 70% tumor cells), efficacy was more pronounced (PFS, 6.1 vs 9.1 mon; HR 0.46; OS, 9.3 v 16.6 mon; HR 0.44). Most common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362.Conclusions: IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile. Clinical trial information: NCT01630083.
