FAST: A randomised phase II study of zolbetuximab (IMAB362) plus EOX vs EOX alone for first-line treatment of advanced CLDN18.2 positive gastric and gastro-oesophageal adenocarcinoma
Mené sur des patients atteints d'un cancer gastrique ou d'un adénocarcinome gastro-oesophagien de stade avancé et surexprimant CLDN18.2, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de l'ajout du zolbétuximab (un anticorps monoclonal ciblant CLDN18.2) à un traitement de première ligne de type EOX (épirubicine, oxaliplatine et capécitabine)
Background : 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 (G/GEJ) and oesophageal adenocarcinoma (EC) patients (≥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 post-enrollment initiation (zolbetuximab+EOX 1000 mg/m2 Q3W, n=85). Primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint Results : In the overall population, both PFS (HR=0.44; 95% 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 vs 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, neutropaenia, anaemia) were grade 1–2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab+EOX vs EOX alone). Conclusions : In advanced G/GEJ and EC patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS vs 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.
Annals of Oncology 2021