Biomarker and pharmacokinetics (PK) analyses of zolbetuximab from the phase 2 GLEAM study in patients (pts) with claudin 18 isoform 2 (CLDN18.2)+ metastatic pancreatic adenocarcinoma (mPAC)

초록

Background: Zolbetuximab is a monoclonal antibody that targets CLDN18.2, a tight junction protein expressed by pancreatic cancer cells. The phase 2 GLEAM study (NCT03816163) compared 1L zolbetuximab + gemcitabine and nab-paclitaxel (GN) to GN in adults with mPAC whose tumors were CLDN18.2+ (defined as ≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining by IHC). We report PK analyses and ad hoc blood biomarker analyses. Methods: Zolbetuximab PK and exposure—response relationships with progressionfree survival (PFS), overall survival (OS), objective-response rate (ORR), safety, and circulating immune-related biomarkers (IL-18, CXCL9, and CXCL10) were assessed. Results: Data from 259 pts were analyzed (data cutoff 3 Sep 2025). Zolbetuximab exposures in mPAC were within the range observed in gastric/gastroesophageal junction adenocarcinoma (G/GEJC), with faster clearance in early cycles (C). ORR was positively associated with exposure; no relationship was observed between exposure and PFS or OS. Higher exposure correlated with increased gastric toxicity. Circulating IL-18, CXCL9, and CXCL10 levels increased more with zolbetuximab + GN vs GN and peaked at C3 in both arms. Circulating biomarker changes were not associated with exposure, demographics, or best overall response. At C3D1, 75 (60%) pts with zolbetuximab + GN and 23 (32%) with GN had increased IL-18 from baseline at or above (≥) median values. Increased IL-18 appeared associated with longer OS in zolbetuximab + GN vs GN. In pts with ≥ 2-fold median IL-18 increase from baseline to C3D1, zolbetuximab + GN (n = 37 [30%]) had mOS of 21.7 months vs 14.1 months with GN (n = 7 [10%]); HR, 0.40 (95% CI, 0.15—1.02). Conclusions: Zolbetuximab exposure in mPAC and G/GEJC was similar, suggesting that lower efficacy in pts with mPAC is a disease- or chemotherapy backbone-specific difference. Zolbetuximab increased immune-related circulating cytokine levels ontreatment. We hypothesize these cytokines and chemokines are related to zolbetuximab’s mechanism of action. Studies are assessing how the baseline tumor microenvironment varies in pts with IL-18 changes and different survival outcomes. Clinical trial identification: NCT03816163. Editorial acknowledgement: Medical writing support, conducted in accordance with Good Publication Practice (GPP 2022) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Jing Xu, PhD, CMPP of Oxford PharmaGenesis Inc., Wilmington, DE, USA, and was funded by Astellas Pharma Inc. Legal entity responsible for the study: Astellas Pharma Inc. Funding: Astellas Pharma Inc.