Background: Current standard of care (SOC) for pts with mNSCLC lacking an actionable mutation includes checkpoint inhibitor (CPI), platinum (PT)-based therapy, or a combination of the two, but is associated with poor outcomes. SG is a Trop-2–directed antibody-drug conjugate. SG monotherapy resulted in a 17% objective response rate (ORR), with a manageable safety profile in pts with mNSCLC who had multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017), and a Ph 2 study is currently ongoing assessing SG+CPI±PT-based therapy (NCT05186974) in treatment-naïve mNSCLC. Etruma (dual adenosine receptor antagonist), dom (anti-TIGIT), and zim (anti–PD-1) are under clinical investigation for antitumor activity. Substudy-01 is part of the VELOCITY-Lung Ph 2 platform study evaluating novel treatment combinations in pts with treatment-naïve mNSCLC. Methods: VELOCITY-Lung (NCT05633667) is an open-label, multicenter, randomized, Ph 2 platform study. Key eligibility criteria for substudy-01 include age ≥18 y; pathologically documented stage IV NSCLC at time of study entry without EGFR, ALK, or other actionable genomic alterations; no prior systemic treatment for mNSCLC; ECOG PS 0-1; any PD-L1 status. Pts previously treated in the (neo)adjuvant setting may be included if therapy was completed ≥12 mo before study drug initiation. Current treatment arms in the preliminary stage are Arm A: dom+zim+SG; Arm B: etruma+dom+zim; Arm C: etruma+zim. Dosing will be as follows: etruma 150 mg po once daily, dom 1200 mg IV q3wk, zim 360 mg IV q3wk, SG 10 mg/kg IV on D1 and D8 of a 21-D cycle. Randomization will be stratified by histology and baseline PD-L1 status (central testing; ≥50% vs < 50%). Pts are randomized equally between treatment arms (arms can be added to evaluate additional novel combinations) in the preliminary stage. Once the expansion stage opens, pts will be randomized based on the number of experimental arms in the expansion stage, the comparator arm, and any newly added preliminary stage treatment arms. Pts will continue to receive treatment until progressive disease, death, unacceptable toxicity, or initiation of a subsequent anticancer therapy. The primary endpoint is ORR assessed by investigator per RECIST v1.1. Secondary endpoints include progression-free survival, duration of response, overall survival, and safety. During the preliminary stage, efficacy will be compared with historical SOC; during the expansion stage, efficacy will be compared with an active comparator arm within the study. Depending on the number of arms being tested in the expansion stage, this study plans to enroll ~69 to 289 patients globally and is open for recruitment. Clinical trial information: NCT05633667.