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Title 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
Authors Sahin, U.
Türeci, Ö.
Manikhas, G.
Lordick, F.
Rusyn, A.
Vynnychenko, Ihor Oleksandrovych  
Dudov, A.
Bazin, I.
Bondarenko, I.
Melichar, B.
Dhaene, K.
Wiechen, K.
Huber, C.
Maurus, D.
Arozullah, A.
Park, J. W.
Schuler, M.
Al-Batran, S.-E.
ORCID http://orcid.org/0000-0002-2339-6509
Keywords advanced gastric cancer
advanced gastroesophageal junction adenocarcinoma
advanced oesophageal adenocarcinoma
zolbetuximab
claudin 18.2
epirubicin
oxaliplatin
capecitabine (EOX)
Type Article
Date of Issue 2021
URI https://essuir.sumdu.edu.ua/handle/123456789/98486
Publisher European Society For Medical Oncology
License Creative Commons Attribution 4.0 International License
Citation 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 / U. Sahin et al. // Annals of Oncology/ 2021. Vol. 32. Is. 5. P. 609-619. https://doi.org/10.1016/j.annonc.2021.02.005.
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 þ oxaliplatin þ capecitabine (EOX, arm 1, n ¼ 84) every 3 weeks (Q3W), or zolbetuximab þ EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n ¼ 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab þ EOX 1000 mg/m2 Q3W, n ¼ 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) ¼ 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR ¼ 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab þ EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-tostrong CLDN18.2 expression in 70% of tumour cells (HR ¼ 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 ¼ 0.58; 95% CI, 0.39- 0.85; P ¼ 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 þ EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade 3 AEs showed no substantial increases overall (zolbetuximab þ 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 þ 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.
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