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Sacituzumab Govitecan Plus Pembrolizumab Demonstrate Encouraging Activity in Patients with mUC Who Progress after Platinum-Based Chemotherapy

Findings from the TROPHY-U-01 cohort 3 study
05 Feb 2024
Urothelial Cancer

In a TROPHY-U-01 cohort 3 study, sacituzumab govitecan in combination with pembrolizumab showed encouraging antitumour efficacy in a platinum-relapsed/refractory population of patients with metastatic urothelial carcinoma (mUC), meeting the primary endpoint. Clinical benefit was observed across all prespecified subgroups, including patients with liver metastases and one or more Bellmunt risk factors, although patient numbers were small in many subgroups, warranting further evaluation in larger trials.

No new safety signals were detected. The study data support further evaluation of sacituzumab govitecan plus immune checkpoint inhibitor (ICI) in mUC according to Dr. Petros Grivas of the Fred Hutchinson Cancer Center, University of Washington in Seattle, WA, US, and colleagues who reported the study findings on 23 January 2024 in the JCO.

The authors wrote in the background that patients with progression on first-line platinum-based chemotherapy have poorer prognosis. Three ICIs are approved by the US Food and Drug Administration (FDA) for post-platinum second-line treatment, including pembrolizumab. Other ICI options in this setting include nivolumab and avelumab. In addition, patients with activating FGFR2 or FGFR3 alterations who progress after platinum-based chemotherapy can receive erdafitinib. Despite these advances, less than one fifth of patients are eligible for the treatment with erdafitinib, and only 18-21% of patients respond to approved second-line ICI; thus, new treatment strategies are needed in this setting.

Two antibody-drug conjugates (ADCs) were recently added to the mUC armamentarium for patients who have progressed after platinum-containing chemotherapy and an ICI, enfortumab vedotin and sacituzumab govitecan. Enfortumab vedotin is a nectin-4–targeting ADC. Sacituzumab govitecan is an ADC composed of a Trop-2 antibody coupled to SN-38, the active metabolite of the topoisomerase 1 inhibitor irinotecan, via a hydrolyzable linker, with a high drug-to-antibody ratio. Trop-2 expression is elevated in several epithelial cancers, including UC. Sacituzumab govitecan received accelerated FDA approval for patients with locally advanced or mUC who have previously received platinum-containing chemotherapy and ICI based on the results of the pivotal TROPHY-U-01 cohort 1 study.

Both pembrolizumab and sacituzumab govitecan as monotherapy have demonstrated antitumour efficacy with manageable, limited-overlapping safety profiles in patients with platinum-relapsed/refractory mUC. It was hypothesised that the combination of these two treatments would be a safe and effective in this setting. To test this hypothesis, the researchers conducted a phase II TROPHY-U-01 cohort 3 study of sacituzumab govitecan plus pembrolizumab in patients with advanced or mUC following progression after platinum-based chemotherapy.

In the article published in the JCO, the study team reports the safety and efficacy outcomes from the primary analysis of the phase II TROPHY-U-01 cohort 3 study. TROPHY-U-01 is a multicohort, open-label phase II study. Patients were ICI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of sacituzumab govitecan once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review. Secondary endpoints included clinical benefit rate (CBR), duration of response (DoR) and progression-free survival (PFS) per central review, and safety.

Cohort 3 included 41 patients whose median age was 67 years, 83% were male; 78% had visceral metastases of whom 29% in liver. With a median follow-up of 14.8 months, the ORR was 41% (95% confidence interval [CI] 26.3 to 57.9) and 20% had complete response rate. CBR was 46% (95% CI 30.7 to 62.6). Median DoR was 11.1 months (95% CI 4.8 to not estimable [NE]). Median PFS was 5.3 months (95% CI 3.4 to 10.2). The median overall survival (OS) was 12.7 months (range, 10.7-NE).

Grade ≥3 treatment-related adverse events occurred in 61% of patients. Most common were neutropenia (37%), leukopenia (20%), and diarrhoea (20%). No treatment-related deaths occurred. The adverse events were predictable and relatively manageable, resulting in a low study drug discontinuation rate (15%). Education and proactive management are recommended for neutropenia, diarrhoea, and other common adverse events using established guidelines.

Limitations inherent to this study design include its single-arm, non-randomised, open-label design and moderate sample size that could lead to potential selection and confounding biases. So, PFS and OS should be interpreted with caution. Because of the single-arm design, the individual contributions of sacituzumab govitecan or pembrolizumab alone cannot be ascertained. Furthermore, a large proportion of patients (44%) did not report race, and molecular biomarkers and patient-reported outcomes were not analyzed.

Additional TROPHY-U-01 cohorts are being assessed, including sacituzumab govitecan monotherapy post-ICI in platinum-ineligible patients with mUC (cohort 2 is closed to accrual and data readouts are expected soon), sacituzumab govitecan plus cisplatin in patients with mUC who are platinum-naïve followed by avelumab plus sacituzumab govitecan as maintenance (cohort 4), sacituzumab govitecan maintenance after first-line cisplatin-based chemotherapy (cohort 5), and continuous sacituzumab govitecan versus continuous sacituzumab govitecan plus zimberelimab (anti–PD1 monoclonal antibody) versus carboplatin plus gemcitabine and avelumab maintenance in first-line cisplatin-ineligible mUC (cohort 6). TROPiCS-04, the phase III confirmatory study of sacituzumab govitecan monotherapy in mUC that has progressed after platinum-based chemotherapy and ICI, is ongoing,

The findings were previously presented in part at the 2023 ASCO Genitourinary Cancers Symposium (16-18 February, San Francisco, CA, US).

The study was supported by Gilead Sciences, Inc.


Grivas P, Pouessel D, Park CH, et al. Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3. JCO; Published online 23 January 2024: DOI: https://doi.org/10.1200/JCO.22.02835

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