Background: The addition of programmed cell death/ligand protein 1 (PD-[L]1) inhibitors to standard chemotherapy has improved outcomes in patients with HER2-negative unresectable or metastatic esophago-gastric adenocarcinomas. Current first-line (1L) treatment for these patients comprises FOLFOX (oxaliplatin, leucovorin, and fluorouracil) and CAPOX (capecitabine and oxaliplatin) chemotherapy, with or without the addition of a PD-1 inhibitor. Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domains (TIGIT), reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) and nivolumab are mAbs that bind to PD-1 on T/NK cells, preventing the immunosuppressive effects of PD-L1 and leading to enhanced immune-mediated tumor cell death. Prior studies (including ARC-7) have demonstrated that the combination of dom + zim is safe, tolerable, and has promising activity in patients with lung cancer and esophago-gastric cancers. This study will investigate whether adding anti-TIGIT therapy to the standard combination of anti-PD-1 therapy and chemotherapy in patients with locally advanced unresectable or metastatic gastric, GEJ, and esophageal adenocarcinoma provides additional clinical benefit. Methods: STAR-221 (NCT05568095) is a global, phase 3, randomized, open-label study. Eligible patients are adults with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma treated in the 1L setting with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with known HER2-positive tumors are not eligible. Approximately 970 patients will be randomized 1:1 into 1 of 2 treatment arms. Patients randomized to Arm A will receive either dom 1600 mg + zim 480 mg every 4 weeks (Q4W) in addition to FOLFOX chemotherapy once every 2 weeks (Q2W) or dom 1200 mg + zim 360 mg once every 3 weeks (Q3W) in addition to CAPOX chemotherapy Q3W. Patients randomized to Arm B will receive either nivolumab 240 mg Q2W + FOLFOX Q2W or nivolumab 360 mg Q3W + CAPOX Q3W. Randomization will be stratified by PD-L1 expression (tumor area positivity [TAP] ≥ 5% vs TAP < 5%), ECOG performance status (0 vs 1), and region (USA, Canada, and EU5 countries vs Asia vs rest of world). The dual primary endpoints are overall survival (OS) in the intent-to-treat population and OS in patients with high PD-L1 expression (TAP ≥ 5%). Secondary endpoints include progression-free survival, objective response rate, duration of response, and safety and tolerability. STAR-221 is currently enrolling globally. Clinical trial information: NCT05568095.