Randomized phase II trial evaluating the efficacy of zolbetuximab in the second-line for claudin18.2 positive advanced gastric/EGJ cancer patients previously treated with zolbetuximab and platinum-based chemotherapy (ZELDA trial).

Abstract

TPS470 Background: Gastric and gastroesophageal adenocarcinomas (GC/GEJC) are common cancers with, particularly in Asia, and the treatment options for advanced/metastatic disease are limited. Zolbetuximab, a first-in-class monoclonal antibody targeting CLDN18.2, has demonstrated significant survival improvement when combined with chemotherapy in the first-line treatment of advanced/metastatic HER2-negative CLDN18.2 positive GC/GEJCs, while the clinical value of continuing zolbetuximab beyond progression is unknown. The ZELDA trial is a randomized, open-label, phase II study designed to evaluate the efficacy and safety of zolbetuximab in combination with nab-paclitaxel and ramucirumab (experimental treatment) compared with nab-paclitaxel plus ramucirumab (control treatment) in patients with previously treated advanced/metastatic CLDN18.2-positive GC/GEJCs. Methods: The ZELDA study is a multicenter, open-label, randomized phase II trial conducted by WJOG/KSCC. Eligible patients are aged ≥18 years, with histologically confirmed advanced or metastatic CLDN18.2-positive adenocarcinoma of the stomach, gastroesophageal junction. Prior treatment with zolbetuximab, oxaliplatin, and fluoropyrimidine for advanced/metastatic disease is required. Patients must have an ECOG performance status of 0 or 1. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate per RECIST 1.1, disease control rate, and safety. The trial includes a safety lead-in part (n=6), which will evaluate tolerability of the experimental regimen (zolbetuximab 400 mg/m² D1,15 + nab-paclitaxel 100 mg/m² D1,8,15 + ramucirumab 8 mg/kg D1,15; q28d). Upon confirmation, patients will be randomized 1:1 to experimental or control treatment. Stratification factors include ECOG performance status (0 vs 1), tumor site (gastric vs EGJ), and prior resection of the primary tumor. A total sample size of 210 patients, which provides 80% power to detect a hazard ratio of 0.77 for overall survival (median 10 vs 13 months), using a one-sided alpha of 0.20 and accounting for 160 events. Biomarker analyses will evaluate expression and other molecular markers, including serum proteomics, gene alterations, and methylation profiles, in relation to treatment efficacy, resistance, and toxicity. Enrollment began in August 2025. Clinical trial information: jRCTs071250038 .