Randomized phase II trial of zolbetuximab as second-line treatment in patients with claudin 18.2-positive advanced gastric/GEJ cancer with previous zolbetuximab exposure: ZELDA

Abstract

Background Zolbetuximab, an anti-claudin 18.2 (CLDN18.2) monoclonal antibody, combined with fluoropyrimidine- and platinum-based chemotherapy, is established as first-line standard of care for patients with CLDN18.2-positive, human epidermal growth factor receptor 2-negative advanced gastric or gastroesophageal junction (GEJ) cancer, based on the phase III SPOTLIGHT and GLOW trials. However, evidence regarding the efficacy and safety of continuing zolbetuximab beyond disease progression remains lacking. Given reports that CLDN18.2 expression is maintained after chemotherapy and the absence of clearly established resistance pathways, continued CLDN18.2-targeted therapy in the second-line setting warrants investigation. Aim To investigate whether the addition of zolbetuximab to second-line nab-paclitaxel plus ramucirumab improves overall survival (OS) in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinoma who have progressed with first-line zolbetuximab-based therapy. Trial design ZELDA (jRCTs071250038) is a multicenter, open-label, randomized phase II (rP2) trial conducted by the West Japan Oncology Group and Kyushu Study Group of Clinical Cancer in Japan. A safety lead-in part (n = 6) confirms the tolerability of the triplet combination (zolbetuximab + nab-paclitaxel + ramucirumab), followed by a rP2 trial (n = 210) with a 1 : 1 allocation to nab-paclitaxel + ramucirumab (arm A, control) or zolbetuximab + nab-paclitaxel + ramucirumab (arm B, experimental). The primary endpoint is OS in the full analysis set. Integrated translational research (ZELDA-TR) is also planned.