Background: Although immune checkpoint inhibitors have improved clinical outcomes in mNSCLC, the majority of patients will experience progression and shorter survival. Thus, an urgent need exists for more effective treatment options in mNSCLC. DOM is an anti-TIGIT IgG1, Fc-silent monoclonal antibody designed to inhibit the interaction between TIGIT and its ligand, CD155, thereby reducing immunosuppression of T cells and natural killer cells and promoting antitumor activity. ZIM is an anti–PD-1 IgG4 monoclonal antibody with demonstrated antitumor activity in vivo and preliminary clinical activity in multiple tumor types. Preliminary studies have shown that dual blockade of TIGIT and PD-(L)1 increases antitumor activity relative to PD-(L)1 inhibition. In ARC-7, a randomized phase 2 study in PD-L1–high, first-line NSCLC, DOM and ZIM in combination recently demonstrated a higher objective response rate (ORR) and longer median progression-free survival (PFS) than ZIM monotherapy. We hypothesize that DOM and ZIM in combination with chemotherapy will improve clinical outcomes in patients with untreated mNSCLC without EGFR or ALK aberrations regardless of PD-L1 expression. Methods: STAR-121 is a phase 3, global, open-label, randomized study to evaluate the safety and efficacy of DOM and ZIM plus chemotherapy vs pembro plus chemotherapy as first-line therapy for patients with mNSCLC with no EGFR or ALK aberrations or other known actionable gene alterations. Approximately 720 patients will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 tumor proportion score ( < 50% vs ≥50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Eligible patients are aged ≥18 with untreated mNSCLC with no EGFR or ALK aberrations. Group A will receive DOM 1200 mg + ZIM 360 mg + platinum-doublet chemotherapy (PT), group B will receive pembro 200 mg + PT, and group C will receive ZIM 360 mg + PT. DOM, ZIM, and pembro will be administered until disease progression (PD) as assessed by blinded independent central review (BICR) per RECIST 1.1 or intolerable toxicity or for up to 35 doses. Study treatment will be administered IV every 3 weeks. PT will be chosen by investigators based on tumor histology and administered for the first 4 cycles, after which, pemetrexed can be continued for patients with nonsquamous histology until PD or intolerable toxicities. The primary endpoints are PFS by BICR and overall survival. Key secondary endpoints are ORR and duration of response by BICR, safety, and quality of life. This study is currently enrolling globally. Clinical trial information: NCT05502237.