Second-Line Combination Study in Urothelial Cancer

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The combination of the antibody-drug conjugate sacituzumab govitecan-hziy and the immune checkpoint inhibitor pembrolizumab yielded antitumor activity as second-line therapy in patients with platinum-refractory, checkpoint inhibitor–naive, metastatic urothelial cancer, according to the results of Cohort 3 of the phase II TROPHY-U-01 trial reported at the 2022 ASCO Genitourinary Cancers Symposium.1

At a median follow-up of 5.8 months, patients treated with the combination had an objective response rate of 34%. There was 1 complete response, 13 partial responses, and 11 patients with stable disease (4 of the 11 had stable disease for at least 6 months).

“These data support further evaluation of antibody-drug conjugate/checkpoint inhibitor combination [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in earlier lines of therapy in a different patient population,” stated lead author Petros Grivas, MD, PhD, of Seattle Cancer Care Alliance, the University of Washington School of Medicine, and Fred Hutchinson Cancer Research Center. “Additional follow-up for survival events and biomarkers is ongoing.”

Two-thirds of patients had some degree of tumor reduction on CT scans [with sacituzumab govitecan plus pembrolizumab]. A number of patients had durable responses.
— Petros Grivas, MD, PhD

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“Metastatic urothelial cancer is associated with a poor outcome, and treatment options are relatively limited, especially in the platinum-refractory setting,” Dr. Grivas told the audience.

Sacituzumab govitecan, a first-in-class antibody-drug conjugate against Trop2, is approved by the U.S. Food and Drug Administration as a salvage therapy for previously treated metastatic urothelial cancer. Dr. Grivas and colleagues sought to evaluate sacituzumab govitecan in combination with an immune checkpoint inhibitor, pembrolizumab, as second-line therapy in Cohort 3 of the multicohort TROPHY-U-01 trial. At the symposium, Dr. Grivas reported interim safety and efficacy results of Cohort 3.

Study Details

Cohort 3 enrolled 41 patients with metastatic urothelial cancer who were checkpoint inhibitor–naive and experienced progressive disease soon following treatment with platinum-based therapies. A total of 83% were male; 54% were White; the median age of patients was 67; 61% had an Eastern Cooperative Oncology Group performance status of 1; 78% had distant metastasis; 68% had visceral metastasis. A total of 49% had at least one Bellmunt risk factor, and 27% had two risk factors.

Patients enrolled in Cohort 3 were treated with sacituzumab govitecan at 10 mg/kg on days 1 and 8 every 21 days and 200 mg of pembrolizumab on day 1 every 21 days. Treatment was continued until the development of unacceptable toxicity or disease progression.

The primary endpoint was objective response rate according to investigator review. Key secondary endpoints included safety, duration of response, progression-free survival, and overall survival.

About half of all enrolled patients had been treated with neoadjuvant or adjuvant platinum-based chemotherapy. In patients with advanced disease treated in the first-line setting, the median time from the last chemotherapy dose to trial screening was 1.6 months. “These patients had very rapid cancer progression after platinum-based chemotherapy,” Dr. Grivas emphasized.

Key Findings

A total of 63% of patients experienced tumor shrinkage, and the clinical benefit rate was 61%. The median time to response was 2 months, and the median duration of response was not reached. Median progression-free survival was 5.5 months, and median overall survival was not reached.

“Two-thirds of patients had some degree of tumor reduction on CT scans,” Dr. Grivas noted.

Responses were seen in patients with visceral metastases and liver metastases (objective response rates 36% and 42%, respectively). Among patients who had a Bellmunt risk factor of 0, 1, and 2, objective response rates were 40%, 35%, and 27.3%, respectively. “A number of patients had durable responses,” he added.

Safety Profile

The most common treatment-emergent (any cause) adverse effects of any grade were diarrhea (76%), nausea (59%), anemia (56%), and neutropenia (44%). Grade 3 treatment-emergent (any cause) adverse events were neutropenia (27%), diarrhea (24%), anemia (20%), and leukopenia (20%).

A total of 68% of patients permanently discontinued treatment, and 32% were still being treated at the time of data cutoff. Reasons for treatment discontinuation included progressive disease (51%), withdrawal of consent (5%), and adverse event (3%).

Grade 3 or 4 treatment-related adverse events were reported in 59% of patients; 39% discontinued sacituzumab govitecan because of treatment-related adverse events. The most common treatment-related adverse events of any grade were diarrhea (71%), nausea (54%), and neutropenia (44%). A total of 25% of patients required steroids for an immune-related adverse event; 15% required topical steroids, and 10% required oral steroids. A total of 29% of patients required granulocyte-macrophage colony-stimulating factor.

Additional TROPHY-U-01 cohorts are being assessed. Cohort 2 is evaluating sacituzumab govitecan as a single agent after first-line checkpoint inhibitor, and Cohorts 4 and 5 are evaluating sacituzumab govitecan in combination with cisplatin without or with avelumab as induction therapy followed by switch maintenance avelumab. 


DISCLOSURE: Dr. Grivas has served as a consultant or advisor to 4D Pharma PLC, AstraZeneca, Astellas Pharma, Bristol Myers Squibb, Dyania Health, EMD Serono, Exelixis, Genentech/Roche, Guardant Health, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, Silverback Therapeutics, and UroGen; and has received grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Gilead Sciences, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, and G1 Therapeutics.


1. Grivas P, Pouessel D, Park CH, et al: TROPHY-U-01 Cohort 3: Sacituzumab govitecan in combination with pembrolizumab in patients with metastatic urothelial cancer who progressed after platinum-based regimens. 2022 ASCO Genitourinary Cancers Symposium. Abstract 434. Presented February 18, 2022.

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