Sacituzumab Govitecan Triplet Elicits Durable Responses in Treatment-Naive Metastatic Urothelial Cancer

The combination of sacituzumab govitecan-hziy (Trodelvy), enfortumab vedotin-ejfv (Padcev), and zimberelimab showed antitumor activity with manageable toxicity in patients with treatment-naive metastatic urothelial cancer, according to interim findings from the phase 1b portion of cohort 7 of the phase 2 TROPHY-U-01 trial (NCT03547973) presented at the 2026 ESMO Congress.¹

At a median follow-up of 12.2 months (range, 1.3-20.8), the objective response rate (ORR) per investigator assessment was 81% (95% CI, 58%-95%) among all treated patients (n = 21). Three patients (14%) achieved a complete response, and 14 patients (67%) experienced a partial response. The clinical benefit rate (CBR), defined as complete or partial response or stable disease lasting at least 6 months, was 86% (95% CI, 64%-97%).

Moreover, the median time to response was 2.5 months (95% CI, 1.2-4.2) and the median duration of response (DOR) was 16.7 months (95% CI, 4.9-not estimable [NE]). The estimated DOR rates at 9 and 12 months were 89% (95% CI, 43%-98%) and 76% (95% CI, 33%-94%), respectively. Tumor shrinkage was observed in all evaluable patients. The median progression-free survival (PFS) was 19.3 months (95% CI, 10.6-NE), with a 12-month PFS rate of 73% (95% CI, 41%-89%); the median overall survival (OS) was not reached (95% CI, 12.2-NE).

"These findings support further investigation of immunotherapy combinations that include antibody-drug conjugates with different mechanisms of action in patients with urothelial carcinoma,” Randy F. Sweis, MD, of the University of Chicago in Illinois, and co-authors, wrote in the presentation.

How was cohort 7 of the TROPHY-U-01 trial in treatment-naive mUC designed?

Cohort 7 enrolled adults with histologically documented, previously untreated, locally advanced unresectable or metastatic urothelial cancer. Patients were required to have measurable disease per RECIST 1.1 and an ECOG performance status of 0 or 1. Previous systemic therapy for locally advanced or metastatic disease was not permitted, although patients who had received curative-intent systemic therapy were eligible if recurrence occurred more than 12 months after their last systemic treatment.

Patients received sacituzumab govitecan at 7.5 mg/kg and enfortumab vedotin at 1.25 mg/kg on days 1 and 8, plus zimberelimab at 360 mg on day 1, of each 21-day cycle. The study comprised a safety lead-in (n = 13) followed by a stage 1 expansion (n = 8) at the 7.5-mg/kg sacituzumab govitecan dose. Primary granulocyte colony–stimulating factor (G-CSF) prophylaxis was mandatory from cycle 1 unless clinically contraindicated.

The primary end points were safety and tolerability and confirmed ORR per investigator assessment. Secondary end points included DOR, CBR, PFS, and OS.

As of the data cutoff date of July 24, 2026, the median patient age was 67 years (range, 39-83), 76% of patients were male, and 67% had an ECOG performance status of 0. Most patients had metastatic disease (76%), 62% had visceral disease, including liver involvement in 19%, and 48% had a creatinine clearance of 30 to less than 60 mL/min.

What was the safety profile of sacituzumab govitecan, enfortumab vedotin, and zimberelimab in this population?

The median treatment durations were 8.0 months (range, 0-18) for sacituzumab govitecan, 7.6 months (range, 0-16) for enfortumab vedotin, and 9.7 months (range, 0-20) for zimberelimab. All patients experienced treatment-emergent adverse effects (TEAEs) and treatment-related adverse effects (TRAEs). Grade 3 or higher TEAEs occurred in 67% of patients, and grade 3 or higher TRAEs occurred in 52%.

TRAEs led to discontinuation of any study drug in 33% of patients, most often enfortumab vedotin (29%), followed by sacituzumab govitecan (19%) and zimberelimab (5%). No TEAEs proved fatal, and no treatment-related deaths occurred; 3 patients died of disease progression. One of 12 evaluable patients (8%) in the safety lead-in experienced a dose-limiting toxicity of febrile neutropenia lasting less than 24 hours.

The most common TRAEs of any grade included fatigue (67%), diarrhea (67%), decreased appetite (62%), alopecia (62%), and nausea (62%). Overall, 95% of patients received primary G-CSF prophylaxis from cycle 1. Grade 3 neutropenia occurred in 3 patients, all during cycle 1, including 1 patient who did not receive primary G-CSF prophylaxis.

What are the next steps for sacituzumab govitecan–based combinations in metastatic urothelial carcinoma?

Ongoing studies of sacituzumab govitecan combined with immunotherapy include the phase 2 DAD/DAD-IO trial (NCT04724018) and the phase 3 ECOG-ACRIN EA8231 trial (NCT06524544).

Ahead of the meeting, Matthew D. Galsky, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York, noted that the activity of the triplet would help clarify whether triplet regimens have a role in metastatic urothelial carcinoma.²

Disclosures: Sweis reported serving as a consultant or advisor for Eisai (personal); receiving institutional financial interests as a local principal investigator from Alentis Therapeutics, Ascendis, Bayer, BMS, Eisai, Genentech/Roche, Immunocore, Loxo Oncology, Merck, Mirati, Moderna, Pyxis Oncology, Scholar Rock, and Xencor; and serving as an institutional steering committee member for Gilead Sciences.

References

1. Sweis RF, Grivas P, Powles T, et al. Sacituzumab govitecan combined with enfortumab vedotin and zimberelimab in treatment-naive metastatic urothelial cancer: interim results from phase 1b TROPHY-U-01 cohort 7. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 4742O.
2. Kret R. VOLGA, DASL-HiCaP Data Highlight Key Genitourinary Cancer Presentations Arriving at ESMO 2026. OncLive. Published October 16, 2026. Accessed October 23, 2026. https://www.onclive.com/view/volga-dasl-hicap-data-highlight-key-genitourinary-cancer-presentations-arriving-at-esmo-2026