Zolbetuximab in CLDN18.2-positive biliary tract cancer after prior systemic therapy: A prospective observational pilot cohort study of early outcomes, safety, and patient-reported quality of life.

Abstract

e16174 Background: CLDN18.2 is a validated therapeutic target in advanced gastric and gastroesophageal junction cancer; however, its role in biliary tract cancer (BTC; intrahepatic or extrahepatic cholangiocarcinoma, or gallbladder carcinoma) remains poorly defined. Immunohistochemical studies suggest that a subset of BTCs express CLDN18.2, but prospective clinical and quality-of-life (QoL) - focused data in BTC are lacking. Patients with advanced, pretreated BTC have limited treatment options after gemcitabine-based therapy. We conducted a prospective observational pilot cohort study to assess feasibility of prospective data capture, early clinical outcomes, safety, and patient-reported QoL among CLDN18.2-positive BTC patients receiving zolbetuximab in the salvage setting. Methods: This single-center, prospective, observational study included adults with unresectable or metastatic BTC treated between January 1, 2025, and December 15, 2025. Eligibility required CLDN18.2 expression in ≥50% of tumor cells (moderate/strong membranous staining) after progression on ≥1 prior systemic therapy. Patients received zolbetuximab in the salvage setting; monotherapy or combination with chemotherapy and dosing schedule (commonly every 3 weeks) were determined by the treating physician. Treatment decisions were at physician discretion; the study did not assign treatment or mandate dosing. The primary endpoint was change in EORTC QLQ-C30 global health status/QoL from baseline to week 6. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), treatment duration, and treatment-emergent adverse events (TEAEs). Results: Seven eligible patients (ECOG 0-2) were included (median age 63 years, range 52-73); all had received ≥2 prior systemic lines. High CLDN18.2 expression (≥75%) was observed in 5/7 patients. ORR was 14% (1 partial response) and DCR was 57%. Median treatment duration was 3.4 months. Mean global health status/QoL improved from 52 to 63 at week 6 (+11 points); 4/7 patients achieved a clinically meaningful ≥10-point improvement. Pain (-15 points) and appetite loss (-12 points) improved most. Any-grade TEAEs occurred in 6/7 patients; grade ≥2 TEAEs occurred in 2/7. No treatment-related deaths occurred. Conclusions: In this prospective, biomarker-selected observational pilot cohort of heavily pretreated BTC, zolbetuximab use was feasible, showed encouraging disease control, and was associated with clinically meaningful QoL improvement. These hypothesis-generating data support further investigation of CLDN18.2-directed strategies in BTC.