Sacituzumab Govitecan/Pembrolizumab show promising anti-tumor activity in metastatic urothelial cancer

Second-line treatment with sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) produced promising anti-tumor activity in patients with checkpoint inhibitor naïve metastatic urothelial cancer, according to results of the cohort 3 of the phase 2 TROPHY-U-01 trial (NCT03547973) presented at the Colloquium on genitourinary cancers 2022.

At a median follow-up of 5.8 months, patients treated with the combination had an objective response rate (ORR) of 34% (95% CI, 20.1% to 50.6%) and a ORR of 38% among evaluable patients. One patient had a complete response (CR), 13 had partial responses (PR), and 11 achieved stable disease. Of those with stable disease, 4 had stable disease for 6 months or more.

“These data support further evaluation of the antibody-drug conjugate/checkpoint inhibitor combination. [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in the first lines of treatment in a different patient population,” according to lead author Petros Grivas, MD, PhD, physician at the Seattle Cancer Care Alliance; Clinical Director of the Genitourinary Cancer Program and Associate Professor in the Division of Medical Oncology at the University of Washington School of Medicine; and Associate Professor in the Division of Clinical Research at the Fred Hutchinson Cancer Research Center. “Additional monitoring of survival events and biomarkers is ongoing.”

As treatment options for patients with metastatic urothelial cancer remain limited and outcomes poor, researchers sought to evaluate other safe and effective options to improve patient responses. Investigators hypothesized that antibody-drug conjugates and checkpoint inhibitors may be a valuable combination strategy capable of providing benefit to patients with metastatic disease.

In Cohort 3 of the open-label, multi-cohort registration study, researchers recruited up to 61 checkpoint inhibitor naïve patients with progressive disease following treatment with platinum-based therapies. The cohort received sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 every 21 days and 200 mg pembrolizumab on day 1 every 21 days. Treatment was continued until patients experienced unacceptable toxicity or disease progression. Patients had to be 18 years of age or older and have an ECOG performance status of 0 or 1. In addition, a creatinine clearance of 30 mL per minute or greater and adequate liver function were required.

The primary endpoint of the study was ORR by investigator review, with key secondary endpoints including safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The majority of patients were male (83%) and the median age was 67 years. Most patients were Caucasian (54%) and had an ECOG performance status of 1 (61%). A total of 49% and 27% of patients had a Bellmunt risk factor of 1 and 2, respectively. Investigators also reported that 49% of patients received neoadjuvant or adjuvant therapy with a median time from completion of most recent prior systemic therapy to screening date of 1.6 months. In terms of best response to prior systemic therapy in the metastatic setting, 1 patient had previously had CR and 2 had PR.

Other study results indicated that 63% of patients experienced tumor shrinkage and the clinical benefit rate was 61% (95% CI, 44.5% to 75.8%). Patients had a median time to response of 2 months and the median DOR was not reached (95% CI, 2.80 – not available). Median PFS was 5.5 months (95% CI, 1.7 – not achieved) and median OS was not achieved.

When examining ORR by subgroup, researchers reported that patients with or without baseline visceral metastases and liver involvement had rates of 41.7% (95% CI 15.17% at 72 .33%) and 31.0% (95% CI, 15.28% to 50.83%), respectively. Additionally, for patients who had a Bellmunt risk factor of 0, 1, and 2, the ORRs were 40.0% (95% CI, 12.16%-73.76%), 35.0% (95% CI, 15.39%-59.22%), and 27.3% (95% CI, 6.02%-60.97%).

The most common adverse reactions (AEs) of any grade in Cohort 3 were diarrhea (76%), nausea (59%) and anemia (56%), with Grade 3 or higher AEs including neutropenia ( 27%), diarrhea (24%), anemia (20%) and leucopenia (20%).

The median duration of treatment was 4 months with sacituzumab govitecan and 3.5 months with pembrolizumab. Sixty-eight percent of patients permanently stopped treatment and 32% were still on treatment at the time of data closure. Patients who discontinued did so due to disease progression (51%), withdrawal of consent (5%) and AE (3%).

Grade 3/4 treatment-related AEs (TRAE) occurred in 59% of patients, with 39% of patients discontinuing sacituzumab govitecan treatment due to a TRAE. The most common all-grade TEARs were diarrhea (71%), nausea (54%) and neutropenia (44%). Twenty-five percent of patients required a steroid for immune-mediated AE, with 15% of patients requiring topical therapy and 10% oral therapy for diarrhea (n= 2), pruritus (n = 1) and maculopapular rash (n = 1). Investigators also reported that 29% of patients required granuloma macrophage colony-stimulating factor.

“[Other] The TROPHY-U-01 cohorts are currently being evaluated. We have cohort 2 looking at sacituzumab govitecan as a single agent after checkpoint inhibition and cohorts 4 and 5 evaluating sacituzumab govitecan in combination with cisplatin more or less avelumab [Bavencio] as induction therapy followed…avelumab [switch maintenance therapy]“Grivas concluded.


Grivas P, Poussel D, Park CH, 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-based regimens (PLT). J Clin Oncol. 2022;40(supplement 6):434. doi:10.1200/JCO.2022.40.6_suppl.434

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