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 adenocarcinomaстатья
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Дата последнего поиска статьи во внешних источниках: 4 марта 2022 г.
Аннотация:Background: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; uponmalignant 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 oesophagealadenocarcinoma 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), orzolbetuximab EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n 77). Arm 3 (exploratory) wasadded after enrolment initiation (zolbetuximab EOX 1000 mg/m2 Q3W, n 85). The primary endpoint wasprogression-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-tostrongCLDN18.2 expression in 70% of tumour cells (HR 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significantimprovement 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 ineither 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 EOXalone).Conclusions: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressingCLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab EOXwas generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase IIIstudies based on clinical benefit observed in the overall population and in patients with moderate-to-strongCLDN18.2 expression in 70% of tumour cells.Key words: advanced gastric cancer, advanced gastroesophageal junction adenocarcinoma, advanced oesophagealadenocarcinoma, zolbetuximab, claudin 18.2, epirubicin, oxaliplatin, capecitabine (EOX)