Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in patients (pts) with claudin 18 isoform 2 (CLDN18.2)+ metastatic pancreatic adenocarcinoma (mPAC): phase II GLEAM study

초록

Background Pts with mPAC have poor prognosis with limited treatment options. Zolbetuximab is an IgG1 monoclonal antibody that targets CLDN18.2, a tight junction protein expressed on pancreatic cancer cells, to induce cytoxicity. We report topline data from the global, open-label, phase 2 GLEAM study (NCT03816163) of 1L treatment of adults with CLDN18.2+ mPAC. Methods Adults with previously untreated mPAC whose tumors were CLDN18.2+ (≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining) were included. Pts were randomly assigned 2:1 to receive 1000 mg/m2 zolbetuximab (C1D1), then 600 mg/m2 every 2 weeks with GN on D1, D8, and D15 of each 28-day cycle, or GN alone until disease progression or other discontinuation criteria were met. Primary endpoints were safety/tolerability and overall survival (OS). Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR) per RECIST v1.1 by investigator; disease control rate (DCR); and duration of response (DOR). Exploratory serum biomarkers were measured by Luminex assay. Results At data cutoff (3 Sep 2025), 585 of 2113 screened pts (27.7%) had CLDN18.2+ tumors; 393 were randomly assigned to zolbetuximab + GN (n = 262) or GN (n=131). Demographics were similar between arms. Median OS was 13.7 vs 13.6 months with zolbetuximab + GN vs GN; HR, 1.00 (95% CI, 0.78–1.29); P = 0.499. Safety and secondary endpoints are reported in table. Levels of proinflammatory IL-18 increased ≥2-fold above the median in 37 pts (30%) with zolbetuximab + GN and 7 (10%) with GN. In these pts, median OS was longer with zolbetuximab + GN vs GN (21.7 vs 14.1 months; HR, 0.40 [95% CI, 0.15–1.02]). Conclusions Blood biomarker results suggest a subset of patients with CLDN18.2+ mPAC may benefit from zolbetuximab. IL-18 levels may be associated with clinical benefit to zolbetuximab in pts with mPAC. 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 Ann Ferguson, PhD, of Oxford PharmaGenesis Inc., Wilmington, DE, and was funded by Astellas Pharma Inc. Legal entity responsible for the study Astellas Pharma Inc. Funding Astellas Pharma Inc.