Scott T. Tagawa, MD
Sacituzumab govitecan demonstrated clinical activity with an overall response rate (ORR) of 29% in patients with heavily pretreated metastatic urothelial carcinoma, according to findings of a cohort from the single-arm phase II TROPHY-U-O1 trial that were presented at the 2019 ESMO Congress.1
The ORR comprised 2 complete responses, 6 partial responses (PRs), and 2 additional PRs pending confirmation. In patients with liver metastases (n = 23), the ORR was 25.0%, lead study author Scott T. Tagawa, MD, stated in a presentation during the meeting. Regarding safety, sacituzumab govitecan was found to be well tolerated with a manageable and predictable safety profile.
“The TROPHY-U-01 study confirms the previously presented clinical activity of sacituzumab govitecan in heavily pretreated patients with advanced urothelial carcinoma. Sacituzumab govitecan was overall well tolerated with a safety profile consistent with prior reports, with the most common toxicity of myelosuppression, which is reasonably managed with growth factors and/or dose reductions,” said Tagawa, Richard A. Stratton Associate Professor in Hematology and Oncology, associate professor of clinical medicine & urology at Weill Cornell Medicine, associate attending physician, NewYork-Presbyterian–Weill Cornell Medical Center. “These data, combined with the prior available data, demonstrate that sacituzumab govitecan has the potential to change the landscape of advanced urothelial carcinoma.”
Patients with metastatic urothelial carcinoma who progress on platinum-based therapy have limited therapeutic options and poor outcomes, with ORRs at approximately 10%. Checkpoint inhibitors have also not been effective in the majority of these patients, emphasizing the need for additional treatments.
Sacituzumab govitecan, a Trop-2–directed antibody–drug conjugate, has also shown significant clinical activity in other solid tumors, such as metastatic triple-negative breast cancer. Trop-2 is an epithelial cell surface antigen that is highly expressed in urothelial cancer.
In the phase I/II single-arm basket study IMMU-132-01, sacituzumab govitecan was evaluated in patients with advanced epithelial cancers, including a metastatic urothelial cancer cohort in which the median number of prior therapies was 2 (range, 1-6). In the overall cohort (n = 45), the ORR was 31% and, in patients who received prior platinum-based therapy and checkpoint inhibitors (n = 15), the ORR was 27%.2
The median progression-free survival (PFS) was 7.3 months (95% CI, 5.0-10.7) and the median overall survival (OS) was 16.3 months (95% CI, 9.0-31.0). The data warranted further investigation and the rationale to develop a phase II trial.
In the open-label, phase II TROPHY-U-01 trial, investigators evaluated sacituzumab govitecan in 2 cohorts: patients with metastatic urothelial cancer who progressed after platinum-based therapy and checkpoint inhibition (n = 100; cohort 1), and those who were ineligible for platinum-based therapy and progressed following prior checkpoint inhibitor treatment (n = 40; cohort 2).
At the 2019 ESMO Congress, Tagawa presented preliminary data from cohort 1, which was a Simon 2-stage design with 90% power to reject the null hypothesis of ≤12% ORR. The preplanned interim analysis was based on an investigator assessment of data as per RECIST v1.1 criteria of cohort 1. Furthermore, the first stage included a prespecified futility stopping rule if ≤4 responses were observed out of 35 patients.
Patients received sacituzumab govitecan at 10 mg/kg on days 1 and 8 every 3 weeks, and treatment was continued until unacceptable toxicity or disease progression. The primary endpoint was ORR; secondary endpoints were safety/tolerability, duration of response, PFS, and OS. The 35 patients included in the interim analysis received ≥1 cycle of sacituzumab govitecan and had ≥1 on-treatment response assessment.
The median age was 64 years (range, 43-90), with 20% of patients ≥75 years. Most patients were male (80%) and white (83%), and more than half had an ECOG performance status of 1 (57%). Of those with visceral metastases, most were in the lung (40%), followed by liver (23%), and other (11%). The median number of prior therapies was 3 (range, 2-6), and the median duration of the last anticancer regimen was 1.6 months (range, 1-60).
At a median follow-up of 4.1 months, results showed that 74% of patients experienced a reduction in tumor size. The median time to onset response was 1.5 months (range, 1.2-2.8). Although preliminary, responses were higher in patients <75 years (n = 8), in those with ≥3 prior anticancer regimens (n = 8), and in patients with 0 to 1 Bellmunt risk factors (n = 10). As of the data cutoff, 8 of the 10 responders have an ongoing response.