In a Cohort 2 of the TROPHY-U-01 study, sacituzumab govitecan demonstrated an objective response rate (ORR) of 32% and a median duration of response (DoR) of 5.6 months in 38 patients with locally advanced (LA) or metastatic urothelial cancer (mUC) who were deemed cisplatin-ineligible at the start of the study, received no previous platinum-based chemotherapy in the metastatic setting, and had progressed on previous immune checkpoint inhibitor (ICI) therapy. Responders in this study had a short median time to achieving an objective response of 1.4 months.
Antitumour activity was observed across multiple subgroups, including those with >2 previous therapies and those with an ECOG performance status (PS) of 1, although sample sizes were small in a few subgroups. Further analysis in larger studies is needed to determine sacituzumab govitecan activity in specific subgroups. Findings are published by Dr. Daniel P. Petrylak of the Yale School of Medicine in New Haven, CT, US and colleagues on 26 August 2024 in the JCO.
The authors wrote in the background that preferred first-line treatment for LA, unresectable, or mUC is cisplatin-based chemotherapy; however, factors like compromised PS and impaired renal function render 30-50% of patients being ineligible. Pembrolizumab is recommended as first-line treatment for patients with LA or mUC ineligible for platinum-based chemotherapy by the US Food and Drug Administration (FDA), but the ORR is only approximately 29%. Single-agent chemotherapy and an antibody-drug conjugate enfortumab vedotin are the preferred next-line therapies for cisplatin-ineligible patients with mUC with progression following ICI.
Enfortumab vedotin monotherapy is approved by FDA in patients with LA or mUC ineligible for cisplatin-based chemotherapy and who have previously received ≥1 previous lines of therapy based on the results from the cohort 2 of the phase II EV-201 study. Enfortumab vedotin demonstrated ORR of 52%. However, 4% of patients died from treatment-related adverse events (TRAEs). Additional safe and effective therapies are needed in this setting.
Sacituzumab govitecan is a Trop-2–directed antibody-drug conjugate with an SN-38 payload, approved for patients with LA or mUC who progressed after platinum-based chemotherapy and ICI. TROPHY-U-01 is a multicohort, open-label phase II study that evaluates the efficacy and safety of sacituzumab govitecan and sacituzumab govitecan combinations in patients with mUC. In Cohort 1, sacituzumab govitecan monotherapy produced ORR of 28% and a manageable safety profile in 113 patients with progression after platinum-based chemotherapy and ICI.
In the latest article published in the JCO, the authors report the primary results from the Cohort 2 of the TROPHY-U-01 study in cisplatin-ineligible patients with mUC who progressed after ICI. Cohort 2 includes patients with LA or mUC who have had progression or recurrence after ICI and were cisplatin-ineligible at study initiation. Patients received sacituzumab govitecan 10 mg/kg on days 1 and 8 of 21-day cycles. The primary endpoint was ORR per central review; secondary endpoints were clinical benefit rate (CBR), DoR, and progression-free survival (PFS) per central review and safety.
Cohort 2 included 38 patients of whom 61% male; median age was 72.5 years and 66% had visceral metastases (29% liver), 50% received platinum-based chemotherapy as previous (neo)adjuvant therapy. At a median follow-up of 9.3 months, ORR was 32% (95% confidence interval [CI] 17.5 to 48.7), CBR was 42% (95% CI 26.3 to 59.2), median DoR was 5.6 months (95% CI 2.8 to 13.3), median PFS was 5.6 months (95% CI 4.1 to 8.3), and median overall survival was 13.5 months (95% CI 7.6 to 15.6).
Grade ≥3 TRAEs occurred in 87% of patients, most commonly neutropenia (34%), anaemia (24%), leukopenia (19%), fatigue (18%), and diarrhoea (16%).
The authors concluded that sacituzumab govitecan monotherapy demonstrated a relatively high ORR with rapid responses. This was feasible with a manageable toxicity profile in cisplatin-ineligible patients who had progression after ICI therapy. Limitations include a moderate sample size and lack of random assignment. These results warrant further evaluation of sacituzumab govitecan alone and in combinations in patients with LA/mUC.
Other TROPHY-U-01 cohorts are being assessed, including Cohort 3 evaluating sacituzumab govitecan plus pembrolizumab in ICI-naive patients with LA/mUC who progressed after previous platinum-based therapies; Cohort 4 evaluating sacituzumab govitecan plus cisplatin followed by sacituzumab govitecan plus avelumab (dose-escalation) maintenance or sacituzumab govitecan plus cisplatin dose-expansion induction and sacituzumab govitecan plus zimberelimab dose-expansion maintenance in patients with cisplatin-eligible, treatment-naive LA or mUC; Cohort 5 evaluating sacituzumab govitecan plus zimberelimab versus avelumab versus zimberelimab in patients with LA or mUC who completed first-line cisplatin plus gemcitabine without progression; Cohort 6 evaluating sacituzumab govitecan versus sacituzumab govitecan plus zimberelimab versus sacituzumab govitecan plus zimberelimab plus domvanalimab versus carboplatin plus gemcitabine followed by switch maintenance avelumab in cisplatin-ineligible patients with treatment-naive LA or mUC.
The TROPiCS-04 randomised phase III trial of sacituzumab govitecan versus single-agent chemotherapy of physician’s choice after progression following previous platinum and ICI therapies has completed accrual.
The study findings were previously presented in part at the 2023 ASCO Genitourinary Cancers Symposium in San Francisco, CA, US (16-18 February 2023).
The study was supported by Gilead Sciences, Inc.
Reference
Petrylak DP, Tagawa ST, Jain RK, et al. TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy. JCO; Published online 26 August 2024. DOI: https://doi.org/10.1200/JCO.23.01720