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 Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, 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 checkpoint inhibitor-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, overall survival, 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% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs 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 treatment-related AEs 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.

Value of copeptin and the S-100b protein assay in ruling out the diagnosis of stroke-induced dizziness pattern in emergency departments.

BACKGROUND: Dizziness is a frequent reason for visiting emergency departments (EDs). Differentiating stroke from other causes is challenging for physicians. The role of biomarkers has been poorly assessed. We evaluated whether copeptin and S100b protein (PS100b) assessment, alone or in combination, could rule out stroke in patients visiting EDs for dizziness. METHODS: We included patients 18 years of age or older, visiting the adult ED of a French university hospital for a new episode of dizziness evolving for less than 72 h. All patients underwent standardized physical examination (HINT [Head Impulse test, Nystagmus, test of skew deviation] maneuvers), copeptin and S-100b protein (PS100) measurement and injected brain imaging. Stroke diagnosis involved diffusion-weighted magnetic resonance imaging or, if not available, neurological examination and contrast brain CT scan compatible with the diagnosis. RESULTS: Of the 135 patients participating in the study, 13 (10%) had stroke. The sensitivity, specificity and positive and negative predictive values of copeptin/PS100 combination were 100% (95%CI, 77-100%), 48% (40-57%), 14% (11-27%) and 100% (94-100%), respectively. Values for copeptin alone were 77% (CI95% 0.50-0.91), 50% (CI95% 0.49-0.58), 14% (CI95% 0.08-0.24), 93% (CI95% 0.87-0.98), and for PS100 alone were 54% (CI95% 0.29-0.77), 97% (CI95% 0.92-0.99), 64% (CI95% 0.35-0.84), 95% (CI95% 0.90-0.98). CONCLUSIONS: Absence of copeptin and PS100 elevation seems to ruling out the diagnosis of stroke in patients visiting the ED for a new episode of dizziness. These results need to be confirmed in a large-scale study.