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

Abstract

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. 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. 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). 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.