TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes

Background Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US FDA approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor (CPI), based on Cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. Patients and methods TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and CPI-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. Results Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2-37.6). Median PFS and OS were 5.4 (95% CI 3.5-6.9) and 10.9 months (95% CI 8.9-13.8), respectively. Occurrence of grade ≥3 treatment-related AEs (TRAEs) and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (*1|*1) in 40%, heterozygous (*1|*28) in 42%, homozygous (*28|*28) in 12%, and missing in 6% of patients. In patients with *1|*1, *1|*28, and *28|*28 genotypes, any grade TRAEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. Conclusions With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.