STAR-121: A Phase III Randomized Study of Domvanalimab and Zimberelimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Untreated Metastatic Non–Small Cell Lung Cancer With No Actionable Gene Alterations

•Dual TIGIT and PD-(L)1 inhibition is a novel strategy in nononcogene–driven mNSCLC.•Domvanalimab is an Fc-silent anti-TIGIT antibody. Zimberelimab blocks PD-1.•STAR-121 will test frontline domvanalimab + zimberelimab + chemo versus pembrolizumab + chemo.•Participants will have untreated non–oncogene-driven mNSCLC with all PD-L1 levels.•The dual primary endpoints are progression-free survival and overall survival. Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non–small cell lung cancer (mNSCLC). The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti–PD-1) plus chemotherapy versus pembrolizumab plus chemotherapy in mNSCLC with no actionable gene alterations. Approximately 720 participants (≥18 years old) with untreated mNSCLC and no EGFR and ALK mutations will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 expression (tumor cells