STAR-221: A randomized, open-label, multicenter, phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.

Samuel J Klempner Mass General Cancer Center, Boston, MA info_outline Samuel J Klempner, Kohei Shitara, Allan Sison, Jennifer Scott, Dana Wishengrad, Jack Ronayne, Joon Rhee, Siddhartha Mitra, Dimitry S. A. Nuyten, Yelena Y. Janjigian, Zev A. Wainberg

Authors Samuel J Klempner Mass General Cancer Center, Boston, MA info_outline Samuel J Klempner, Kohei Shitara, Allan Sison, Jennifer Scott, Dana Wishengrad, Jack Ronayne, Joon Rhee, Siddhartha Mitra, Dimitry S. A. Nuyten, Yelena Y. Janjigian, Zev A. Wainberg Organizations Mass General Cancer Center, Boston, MA, National Cancer Center Hospital East, Kashiwa, Japan, Arcus Biosciences, Hayward, CA, Gilead Sciences, Inc., Foster City, CA, Memorial Sloan Kettering Cancer Center, New York, NY, UCLA School of Medicine, Los Angeles, CA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Arcus Biotech 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.

Clinical