Abstract B016: Updated Safety, Efficacy and Biomarker Analysis from the Phase I Study of Givastomig, a Novel Claudin 18.2/4-1BB Bispecific Antibody, in Claudin 18.2 Positive Advanced Gastroesophageal Carcinoma (GEC)

Abstract Background Claudin 18.2 (CLDN18.2) is a validated target in GEC, but novel approaches are needed. Givastomig/ABL111 (giva) is a first-in-class, bispecific antibody targeting tumoral CLDN18.2 and 4-1BB on adjacent T cells, preferentially activating T cells in the tumor microenvironment. Previously, the monotherapy phase 1 data showed that giva was safe and well tolerated in heavily pretreated GEC patients (pts). Here we report updated safety, efficacy, and biomarker data in GEC. Methods The study included dose escalation and dose expansion cohorts. During escalation, pts with solid tumors irrespective of CLDN18.2 expression received giva intravenously every 2 weeks (Q2W) across 8 dose levels (0.1-15 mg/kg), and every three weeks (Q3W) at 18 mg/kg. During expansion, CLDN18.2-positive (CLDN18.2+, ≥1% of tumor cells with ≥1+ intensity by immunohistochemistry) GEC pts were included. Differences in objective response rate (ORR) and disease control rate (DCR) between CLDN18.2-high pts (≥ 75% tumor cells of IHC 2+/3+) and CLDN18.2-low pts were evaluated by Chi-square test. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards. Outcomes for CLDN18.2+ GEC pts at doses ≥ 5 mg/kg are reported here. Results As of June 10, 2025, 45 pts with GEC received giva at 5 mg/kg (n=7), 8 mg/kg (n=5), 12 mg/kg (n=21), and 15 mg/kg (n=6) Q2W and 18 mg/kg Q3W (n=6). Pts had received a median of 3 prior therapies, including 74% with prior programmed death-(ligand) 1 inhibitor. No new safety signal was identified with longer follow up. No dose limiting toxicities were observed. Common treatment-related adverse events (≥15%, any grade/grade 3) included anemia (27%/9%), white blood cell count decrease (22%/7%), nausea (20%/2%), and ALT increase (16%/2%), AST increase (16%/4%). Partial responses (PR) were observed in 8 pts (1 PR each at 5 and 8 mg/kg, 4 PRs at 12 mg/kg, and 2 PRs at 18 mg/kg) with an ORR of 18%. CLDN18.2 expression in responders ranged from 11% (1+, 10%; 2+, 1%) to 100% (2+, 10%; 3+, 90%). Stable disease was observed in 14 pts (DCR 49%). 2 (4%) pts are ongoing, with 1 PR at 8 mg/kg at 33 months (mo) and 1 PR at 18 mg/kg at 10 mo. The median PFS (mPFS) and median OS (mOS) are 2.96 mo (95% CI 1.71-3.91) and 7.49 mo (95% CI 4.96-12.5), respectively. There is no statistical difference in ORR, DCR, PFS, or OS between CLDN18.2-high pts (n=21) and CLDN18.2-low pts (n=24): ORR 19% vs. 17% (p=1.00), DCR 57% vs. 42% (p=0.46), mPFS 3.68 mo vs. 1.84 mo, PFS hazard ratio (HR) 0.87 (p=0.67), and mOS 7.49 mo vs. 7.49 mo, OS HR 0.88 (p=0.74), respectively. Conclusions Giva was well tolerated up to 15 mg/kg Q2W and 18 mg/kg Q3W and continues to show encouraging monotherapy activity in heavily pre-treated GEC pts with a wide range of CLDN18.2 expression. Giva may have the ability to target pts with lower CLDN18.2 expression compared with other CLDN18.2 agents and is currently being tested in 1L GEC in combination with immunochemotherapy (NCT04900818). Citation Format: Samuel J. Klempner, Lin Shen, Farshid Dayyani, Jeremy Kratz, Xinjun Liang, Funan Liu, Zenning Wang, Laura Feller, Eugenia Girda, Hongming Pan, Sunnie Kim, Yanhong Deng, Ting Deng, Tianshu Liu, John Powderly, Kristen Spencer, Reva Schneider, Jordan Berlin, Claire (Cong) M. Xu, Christoph M. Ahlers, Xuejun M. Liu, Peter Sabbatini, Jinyoung Park, Yangmi Lim, Juyeun Jeon, Yuan Meng, Geoffrey Ku. Updated Safety, Efficacy and Biomarker Analysis from the Phase I Study of Givastomig, a Novel Claudin 18.2/4-1BB Bispecific Antibody, in Claudin 18.2 Positive Advanced Gastroesophageal Carcinoma (GEC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B016.