ASCO GU 2022: TROPHY-U-01 Cohort 3: Sacituzumab Govitecan in Combination with Pembrolizumab in Patients with Metastatic Urothelial Cancer Who Progressed After Platinum-Based Regimens

(UroToday.com) The 2022 GU ASCO Annual meeting included a urothelial carcinoma oral abstract session featuring Dr. Petros Grivas and colleagues presenting results of TROPHY-U-01 Cohort 3, sacituzumab govitecan in combination with pembrolizumab in patients with metastatic urothelial cancer who progressed after platinum-based regimens. Outcomes of patients with metastatic urothelial carcinoma are poor with an estimated 5-year survival rate of ~15%. Unfortunately, outcomes remain poor and treatment options are relatively limited for patients with disease progression on platinum-based chemotherapy. Checkpoint inhibitors are standard therapy for patients with metastatic urothelial cancer after platinum-based regimens, with limited long-term disease control. Sacituzumab govitecan is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolysable linker. In the TROPHY-U-01 registration phase 2 trial, sacituzumab govitecan monotherapy demonstrated significant activity and manageable safety in patients with metastatic urothelial cancer who progressed after prior platinum-based chemotherapy and checkpoint inhibitors, with a 27% objective response rate (ORR) and median overall survival of 11 months.¹

Antibody drug conjugates can induce immunogenic cell death, possibly resulting in additive or synergistic activity when combined with checkpoint inhibitors. Such combination strategy (enfortumab vedotin + pembrolizumab) was assessed in patients with cisplatin-ineligible metastatic urothelial carcinoma in the EV-103 cohort A trial, with preliminary results suggesting favorable safety and efficacy with enfortumab vedotin + pembrolizumab in the first-line setting. At GU ASCO 2022, Dr. Grivas presents the interim efficacy and safety results of combining sacituzumab govitecan with pembrolizumab as second-line therapy in checkpoint inhibitor-naive patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy (cohort 3).

TROPHY-U-01 is a multicohort, open-label, global phase 2 trial. Eligible patients had measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and creatinine clearance ≥30 mL/min. The recommended phase 2 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. The primary endpoint for TROPHY-U-01 cohort 3 was ORR by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The key secondary endpoints included investigator-assessed ORR, clinical benefit rate [complete response (CR) + partial response (PR) + stable disease], progression-free survival (PFS), and safety. The trial design for TROPHY-U-01 is as follows: 

With >=13 responses observed, the null hypothesis of true ORR <= 20% would be rejected in 1-sided alpha level of 0.05.

At the time of data cutoff, 41 patients received at least a dose of sacituzumab govitecan at the RP2D (10 mg/kg). Of these 41 patients, the median age was 67 years (range: 46–86), 83% were men, 61% were ECOG performance status 1, 76% had ≥1 Bellmunt risk factor, and the median number of prior anticancer regimens was 1 (range: 1–3). At a median follow-up of 5.8 months, the investigator-assessed ORR was 34% (95% CI 20.1–50.6; 1 CR; 13 PR), clinical benefit rate was 61% (95% CI 44.5–75.8), median PFS was 5.5 months (95% CI 1.7-not reached), and median OS was not reached. The median time to response was 2.0 months (95% CI 1.3–2.8) and median duration of response was not reached (95%CI 2.8 – not reached). There were 63% of patients that had tumor shrinkage:

The patient response assessment from the start of treatment to progression is as follows: 

The most common treatment-emergent adverse events were diarrhea (76%), nausea (59%), anemia (56%), neutropenia (44%), and asthenia (41%). Treatment-related grade ≥3 adverse events occurred in 59% of patients. Key grade ≥3 treatment-emergent adverse events of any cause included diarrhea (24%), anemia (20%), febrile neutropenia (10%), fatigue (7%), and asthenia (5%). Two patients discontinued treatment due to treatment-related adverse events and there were no treatment-related deaths. Limitations noted by Dr. Grivas include the small sample size, short follow-up, and lack of randomization.

Dr. Grivas concluded his presentation of the TROPHY-U-01 cohort 3 study with the following take-home messages:

• Sacituzumab govitecan in combination with pembrolizumab demonstrated encouraging ORR (34%) and clinical benefit rate (61%), with an overall manageable safety profile with no new safety signal in checkpoint inhibitor-naive patients who progressed after prior platinum-based chemotherapy
• At 5.8 months of median follow-up, the median duration of response and median OS were not reached
• The data support further evaluation of sacituzumab govitecan plus checkpoint inhibitors in metastatic urothelial cancer
• Additional follow-up and biomarker evaluation is ongoing
• Other TROPHY-U-01 cohorts are being assessed including sacituzumab govitecan post checkpoint inhibitors in platinum-ineligible patients with metastatic urothelial carcinoma (cohort 2), sacituzumab govitecan + cisplatin (cohort 4), and sacituzumab govitecan + cisplatin + avelumab (cohort 5) in platinum-naïve patients (both followed by avelumab switch maintenance)

Co-Authors: Damien Pouessel, Chandler H. Park, Philippe Barthélémy, Manojkumar Bupathi, Daniel P. Petrylak, Neeraj Agarwal, Aude Flechon, Chethan Ramamurthy, Nancy B. Davis, Alejandro Recio-Boiles, Scott T. Tagawa, Cora N. Sternberg, Astha Bhatia, Cabilia Pichardo, Trishna Goswami, Yohann Loriot

1. Tagawa ST, Balar AV, Petrylak DP, et al. Metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485.