Astellas Pharma (TSE: 4503) has dosed the first patient in a Phase III trial of ASP2138, its subcutaneously administered CLDN18.2 × CD3 bispecific antibody, in first-line CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The trial tests whether layering a T-cell engager onto the combination of chemotherapy and Merck's Keytruda (pembrolizumab) can improve on outcomes that remain poor despite recent advances in the biomarker-selected population. The median progression-free survival on non-CLDN18.2-directed standard of care in this population remains 6 to 7 months, per Astellas' cited reference to KEYNOTE-859 data.
ASP2138 simultaneously binds CLDN18.2 on tumor cells and CD3 on T cells, physically bridging the two to activate cytotoxic killing. Unlike Astellas' own approved CLDN18.2-directed monoclonal antibody Vyloy (zolbetuximab-clzb), which depletes tumor cells through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, ASP2138 recruits T cells directly. The subcutaneous route also distinguishes it from the intravenous infusions required by all currently approved agents in this setting.
The randomized, double-blind, placebo-controlled study plans to enroll 570 participants across multiple countries. The experimental arm receives ASP2138 plus chemotherapy (CAPOX or mFOLFOX6) with pembrolizumab; the control arm receives placebo plus chemotherapy with or without pembrolizumab. Co-primary endpoints are overall survival and progression-free survival. Phase I/Ib data presented at ESMO 2025 provided the proof of concept that supported Phase III initiation, with first clinical results covering monotherapy and combination cohorts in CLDN18.2-positive gastric and GEJ adenocarcinoma.