Zolbetuximab + pembrolizumab and chemotherapy as first-line treatment for patients with CLDN18.2-positive, HER2-negative, PD-L1-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma: Phase 3, double-blind, randomized trial (LUCERNA).

TPS473 Background: The anti-CLDN18.2 antibody zolbetuximab + first-line chemotherapy demonstrated longer progression-free survival (PFS) and overall survival (OS) versus placebo + chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma whose tumors were CLDN18.2-positive (Shitara Lancet 2023; Shah Nat Med 2023; Shitara & Shah NEJM 2024). The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab + first-line chemotherapy demonstrated longer OS versus placebo + chemotherapy in patients with HER2-negative, LA or mG/GEJ adenocarcinoma whose tumors had a programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 (Rha Lancet Oncol 2023). Early reports from the ongoing phase 2 ILUSTRO trial (NCT03505320) suggest encouraging activity with zolbetuximab + third-line or later anti-PD-1 therapy (Klempner Clin Cancer Res 2023); ILUSTRO is also evaluating zolbetuximab + first-line chemotherapy and anti-PD-1 therapy. Methods: This phase 3, double-blind, randomized study aims to enroll ~500 adult patients with previously untreated, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive (defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining using the VENTANA CLDN18 [43-14A] RxDx Assay) and have a PD-L1 CPS ≥1. Patients will be randomly assigned 1:1 to receive IV zolbetuximab (800 mg/m 2 on cycle 1 day 1 followed by 400 mg/m 2 every 2 weeks or 600 mg/m 2 every 3 weeks [Q3W]) + IV pembrolizumab (200 mg Q3W or 400 mg every 6 weeks) and either a capecitabine and oxaliplatin regimen (CAPOX) or a modified folinic acid, fluorouracil, and oxaliplatin regimen (mFOLFOX6) or placebo + pembrolizumab and CAPOX/mFOLFOX6 for four 42-day cycles. Patients can continue beyond cycle 4 with zolbetuximab/placebo + pembrolizumab, and capecitabine or folinic acid and fluorouracil at investigator’s discretion, until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Randomization will be stratified by region (Asia vs non-Asia) and CPS (≥1 to