There remains an unmet need for additional treatment options for 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 are claudin 18 isoform 2 (CLDN18.2)-positive and programmed death-ligand 1 (PD-L1)-positive. The phase 2 ILUSTRO trial previously demonstrated promising clinical activity with the combination of zolbetuximab plus chemotherapy and checkpoint inhibitor therapy in patients with HER2-negative, LA unresectable, or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive, warranting further exploration. In LUCERNA, a multicenter, double-blind, phase III trial, patients with HER2-negative, LA unresectable, or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive and PD-L1-positive will be randomly assigned 1:1 to either first-line zolbetuximab plus pembrolizumab and chemotherapy (a capecitabine and oxaliplatin regimen, CAPOX; or a modified folinic acid, fluorouracil, and oxaliplatin regimen, mFOLFOX6) or placebo plus pembrolizumab and chemotherapy. The primary endpoint is overall survival. Key secondary endpoints are progression-free survival and objective response rate. Additional secondary endpoints include duration of response and safety. The results of this trial have the potential to support a new standard-of-care option in this patient population.