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).

Abstract

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 <10 vs ≥10). The primary endpoint is OS. Key secondary endpoints are PFS and objective response rate per RECIST v1.1 by investigator assessment. Additional secondary endpoints are duration of response per RECIST v1.1 by investigator assessment, safety, pharmacokinetics, and immunogenicity of zolbetuximab. Exploratory endpoints are biomarker expression, health-related quality of life, and PFS after subsequent therapy. Enrollment is ongoing across global sites. Clinical trial information: NCT06901531 .