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Sacituzumab govitecan plus pembrolizumab in patients with metastatic urothelial cancer progressing after platinum-based regimens

For patients with urothelial cancer who progress on platinum-based regimens, outcomes remain poor and treatment options are limited. In TROPHY-U-01, sacituzumab  govitecan in combination with pembrolizumab demonstrated an encouraging objective response rate and clinical benefit rate, with an overall manageable safety profile in checkpoint inhibitor-naive patients who progressed after prior platinum-based chemotherapy.

Outcomes for patients with metastatic urothelial cancer (mUC) are poor with an estimated 5-year survival rate of approximately 15%. To date, platinum-based chemotherapy followed by avelumab maintenance is the standard of care for most patients in the front-line setting. For patients who progressed or recurred on/after platinum-based regimens, several immune checkpoint inhibitors (ICIs) are approved. More recently, also antibody-drug-conjugates (ADC) such as sacituzumab govitecan and enfortumab vedotin have been added to the therapeutic armamentarium for platinum-refractory disease. Unfortunately, outcomes remain poor and treatment options are relatively limited for patients with UC progressing on platinum-based regimens. Therefore, additional safe and effective treatment options, including rational combination strategies are needed to improve clinical outcomes. Sacituzumab govitecan (SG) is a first-in-class Trop-2-directed ADC. ADC and ICI combinations may benefit patients with mUC. At ASCO GU 2022, interim efficacy and safety results from Cohort 3 of the TROPHY-U-01 study of SG with pembrolizumab as second-line therapy in ICI-naïve patients with mUC who progressed on/after platinum-based chemotherapy, were presented.

Study design

TROPHY-U-01 is a registrational, open-label, multicohort phase II trial in patients with mUC. In Cohort 3 of the study, mUC ICI-naïve patients who progressed after prior platinum-based therapies received SG 10 mg/kg on days 1 and 8, every 21 days plus pembrolizumab 200 mg on day 1 of each 21-day cycle. Patients received treatment until progression or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR) by investigator review per RECIST 1.1 criteria. The recommended phase II dose (RP2D) was determined during a 10-patient safety lead-in, and additional patients were enrolled at the RP2D in a Simon 2-stage design. A total of 41 patients were enrolled at RP2D of SG and with at least 13 responses observed, the null hypothesis of true ORR ≤ 20% would be rejected with 1-sided α level of 0.05.


Median age of study participants was 67 years, 61% had an ECOG performance status of 1, 12% had haemoglobin levels below 10 g/dl and 78% had distant metastasis. Furthermore, 68% of patients had received prior cisplatin based chemotherapy, about half of the patients had one Bellmunt risk factor and 27% had two risk factors. Fifty-one percent of patients received chemotherapy for metastatic disease in the front-line setting. After a median follow-up of 5.8 months, the investigator-assessed ORR was 34% (95%CI: 20.1–50.6), with one complete response and 13 partial responses. Additionally, 11 patients had stable disease as best response, with a clinical benefit rate of 61%. The median time to response was two months and the mediation duration of response was not yet reached. The median progression-free survival was 5.5 months and the median overall survival was not reached. Overall, approximately two thirds of patients (63%) achieved some degree of tumour shrinkage. Objective responses were observed across age, race, ethnicity and ECOG PS subgroups. The ORR in patients with baseline visceral metastasis with liver involvement was 41.7%

The most common treatment-emergent adverse events (TEAEs) were diarrhoea (76%), nausea (59%), anaemia (56%), neutropenia (44%), and asthenia (41%). Median treatment duration was 4 months for SG and 3.5 months for pembrolizumab. The most common reason for treatment discontinuation was progressive disease (51%) and only one patient withdrew due to an adverse event. Treatment-related grade 3-4 AEs (TRAEs) occurred in 59% of patients. The most common TRAEs were diarrhoea (71%), nausea (54%), neutropenia (44%) and anaemia (41%). Ten patients (25%) received steroids for immune-related adverse events (topical in six patients, oral in four patients). No treatment-related death occurred.


In this platinum-refractory population, SG plus pembrolizumab showed encouraging antitumour efficacy. In addition, the combination had a manageable safety profile with no new safety signals and no increase in systemic steroid-requiring immune-related adverse event rate. These data support further evaluation of SG plus ICI in patients with mUC who progressed on/after platinum-based chemotherapy and earlier lines of therapy. Additional follow-up and biomarker evaluation are ongoing.


Grivas P, et al. TROPHY-U-01 Cohort 3: Sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. Presented at ASCO GU 2022; Abstract 434.

Speaker Petros Grivas

Petros Grivas

Petros Grivas, MD, PhD, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, USA


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