Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 via a proprietary hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). The results led to accelerated FDA approval of SG for this population. ZIM (anti-PD-1) and DOM (anti-TIGIT) are CPIs under clinical investigation for anti-tumor activity. Cohort 6 of TROPHY-U-01 trial (C6) will assess SG monotherapy vs SG plus CPI combinations (SG + ZIM; SG + ZIM + DOM) vs CARBO/GEM followed by avelumab maintenance in treatment naive cis-ineligible pts with locally advanced or mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. C6 includes pts with cis-ineligible unresectable locally advanced or mUC who are ≥18 y; have an ECOG performance status 0-1; have available tissue for biomarker testing; have no prior mUC therapy, except (neo)adjuvant chemotherapy with recurrence >12 mo from completion; are CPI-naive or >12 mo from completion; have adequate hematologic and hepatic function; and have creatinine clearance ≥30 mL/min. A safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk. A second safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk + DOM 1200 mg q3wk. After the safety lead-in, pts will be randomized 1:2:2:2 to: Arm 1: SG 10 mg/kg on D1 and D8 of a 21-D cycle; Arm 2: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk; Arm 3: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk and DOM 1200 mg q3wk; and Arm 4: CARBO (AUC 4.5-5) on D1 of each 21-D cycle + GEM 1000 mg/m² on D1 and D8 of each 21-D cycle for the first 4-6 cycles followed by switch maintenance avelumab 800 mg q2wk in the absence of progression. All pts will continue treatment until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per central review based on RECIST 1.1. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate by central review and investigator review, as well as ORR by investigator review, and OS, and safety and tolerability (Arms 1-3). C6 aims to enroll an estimated 226 pts. With 60 subjects each in Arms 2-4, a comparison of Arm 2 or 3 vs Arm 4 will have ~88% power at one-sided α of 0.05 to demonstrate an improvement in ORR, with a null hypothesis of ORR 40% for Arms 2-3 and an alternative hypothesis of ORR at 65% for Arms 2-4. Clinical trial information: NCT03547973.