Safety and preliminary efficacy results of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with solid tumors and gastric or gastro-esophageal tumors: A phase 1 dose escalation and expansion study.

2519 Background: CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors. Methods: Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 µg/kg to 600 µg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10µg/kg to 600 µg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4). Conclusions: IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458 .