TROPHY-U-01 Cohort 4 (C4): Sacituzumab govitecan (SG) in combination with cisplatin (cis) as first-line (1L) therapy, followed by maintenance avelumab plus (+) SG or zimberelimab (zim) plus SG in patients (pts) with treatment (Tx)-naive metastatic urothelial cancer (mUC).

TPS4611 Background: SG is a Trop-2–directed antibody-drug conjugate. In the TROPHY-U-01 study, SG monotherapy showed a 27% objective response rate (ORR) and 10.9 months median overall survival (OS) with an overall manageable safety profile in pts with mUC who received platinum (PT)-containing chemotherapy and a checkpoint inhibitor (CPI), resulting in accelerated FDA approval in this population. PT-based chemotherapy followed by avelumab maintenance is standard 1L therapy in pts with Tx-naïve mUC. Zim (anti–PD-1) is a CPI under clinical investigation for antitumor activity. C4 of TROPHY-U-01 will evaluate safety, tolerability, and clinical activity of SG+cis followed by maintenance avelumab+SG or zim+SG in cis-eligible pts with Tx-naïve mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 study. C4 will evaluate 1L SG in combination with cis in pts with cis-eligible mUC or unresectable locally advanced disease. Eligibility requirements include ECOG PS 0-1; no prior anticancer monoclonal antibody within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic and hepatic function. Pts will be treated with cis at 70 mg/m 2 on D1 of 21-D cycles (if creatinine clearance [CrCl] ≥60 mL/min) or at an optional split dose of 35 mg/m 2 on D1 and D8 of 21-D cycles (if CrCl 50-59 mL/min), followed by SG (5, 7.5, or 10 mg/kg, based on 10-pt safety lead-in of a 3+3 design) on D1 and D8 of 21-D cycles. Granulocyte colony-stimulating factor support is not allowed in the safety lead-in but was permitted during escalation and expansion. SG+cis will continue for up to 6 cycles, followed by maintenance (4 to 8 wk after last induction dose of SG+cis and when RP2D is determined) in the absence of progression. Dose escalation maintenance consists of avelumab 800 mg q2w, then SG 10 mg/kg on D1 and D8 of 21-D cycles. Dose expansion maintenance consists of zim 360 mg (D1 of a 21-D cycle) and SG 10 mg/kg (D1 and D8 of 21-D cycles) and will begin once safety lead-in of 6-8 pts receiving zim+SG of a 21-D cycle in Cohort 5 is deemed safe and completed. Pts will continue Tx until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per RECIST v1.1 by central review. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per central review and investigator assessment. OS and safety will also be evaluated. All statistical analyses will be performed using a two-sided hypothesis test approach at the overall 5% level of significance. Time to event endpoints will be assessed via the Kaplan-Meier method. Enrollment is ongoing; up to 57 pts expected across ~120 sites in North America and Europe. Clinical trial information: NCT03547973 .