A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3.

PURPOSE: Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2-directed antibody-drug conjugate with US Food and Drug Administration-accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Patients were CPI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of SG once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per central review. Secondary end points included clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS) per central review, and safety. RESULTS: Cohort 3 included 41 patients (median age 67 years; 83% male; 78% visceral metastases [29% liver]). With a median follow-up of 14.8 months, the ORR was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), CBR was 46% (95% CI, 30.7 to 62.6), median DOR was 11.1 months (95% CI, 4.8 to not estimable [NE]), and median PFS was 5.3 months (95% CI, 3.4 to 10.2). The median overall survival was 12.7 months (range, 10.7-NE). Grade ≥3 treatment-related adverse events occurred in 61% of patients; most common were neutropenia (37%), leukopenia (20%), and diarrhea (20%). CONCLUSION: SG plus pembrolizumab demonstrated a high response rate with an overall manageable toxicity profile in patients with mUC who progressed after platinum-based chemotherapy. No new safety signals were detected. These data support further evaluation of SG plus CPI in mUC.

Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.