PRELIMINARY EVIDENCE suggests that the antibody-drug conjugate sacituzumab govitecan is active in patients previously treated with chemotherapy or checkpoint inhibitor therapy for metastatic urothelial cancer. These results from a phase I/II basket study of this agent were presented at the 2019 Genitourinary Cancers Symposium.¹

In a cohort of 45 heavily pretreated patients with relapsed or refractory metastatic urothelial cancer, the objective response rate was 31%. In patients with liver metastases, the objective response rate was 33%. The objective response rate was 27% in checkpoint inhibitor–treated and platinum-treated patients.

“These responses were seen with reasonable drug tolerance, a manageable and predictable safety profile, and a relatively low rate of discontinuations due to adverse events and none due to neutropenia,” said lead author Scott T. Tagawa, MD, Associate Professor of Clinical Medicine and Urology, and Medical Directorof the Genitourinary Oncology Research Program, Meyer Cancer Center, Weill Cornell Medicine and NewYork-Presbyterian Medical Center. “We believe this drug deserves further study.”

“These responses [to sacituzumab govitecan] were seen with reasonable drug tolerance, a manageable and predictable safety profile, and a relatively low rate of discontinuations due to adverse events.”

— Scott T. Tagawa, MD

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Sacituzumab govitecan is a novel antibody-drug conjugate directed against Trop-2, an antigen present on the cell surface of several types of epithelial cancers, including urothelial cancer. The anti–Trop-2 antibody has a linker designed to deliver the “payload” of the active metabolite of irinotecan (ie, SN-38) to tumor cells. SN- 38 is estimated to be 1,000 times more potent than irinotecan.

Study Details

THE 45 PATIENTS enrolled in the metastatic urothelial cancer dose-expansion cohort were “treatment refractory beyond the standard of care,” Dr. Tagawa told listeners. They were treated with the recommended phase II dose of sacituzumab govitecan—10 mg/kg on days 1 and 8 every 21 days—with restaging scans every 8 weeks. Treatment was continued until disease progression or unacceptable toxicity.

The median age of patients was 67 years. The majority were male, white, and had an Eastern Cooperative Oncology Group Performance Status of 1. Three-quarters of the patients had visceral metastases, and one-third of these patients had liver metastasis. The median number of prior anticancer regimens was 2 (range, 1–6). Sixty-two percent received up to 2 prior lines of therapy and 38% received 3 prior lines or more. A total of 17 patients had prior checkpoint inhibitor therapy and 71% of them had at least 3 prior lines of therapy.

The median duration of follow-up was approximately 15.7 months. The most common adverse events were diarrhea (69%), nausea (67%), fatigue (58%), and neutropenia (51%). A total of 25% of patients received at least 1 dose of growth factor support.

“Grade 3 and 4 adverse events were largely laboratory abnormalities. The most frequent grade ≥ 3 adverse events were neutropenia and anemia (13%). Five patients discontinued treatment due to potential drug-related adverse events, none due to neutropenia,” Dr. Tagawa said. “There were no treatment-related deaths.”

Response Rates

FOR THE PRIMARY endpoint, the objective response rate in this heavily pretreated population was 31%. One-third of patients with liver metastasis responded (5 of 15), as did 23.5% of those who had received a prior checkpoint inhibitor (4 of 17). According to the number of prior lines of therapy, the objective response rate was 39.3% (11 of 28) in patients receiving up to 2 prior lines and 17.6% (3 of 17) in those receiving at least 3 prior lines. From the waterfall plot, 68.9% (31 of 45) had a decrease in the sum of measurable target lesions.

“The majority of patients had some decrease in tumor burden and responses were seen early,” Dr. Tagawa continued.

The median time to onset of response was 1.9 months and the duration of response was 12.9 months. Overall, the median progression-free survival was 7.3 months and the median overall survival was 16.3 months.

At the meeting, Dr. Tagawa showed slides of patients with remarkable responses to sacituzumab govitecan. One patient with inoperable high-grade papillary urothelial cancer pretreated with 4 lines of therapy had a 76% reduction in tumor burden. A second case had a 32% reduction in lung metastases and complete resolution of 2 liver metastases.

“We believe the activity in this modest subset of patients deserves further study, so the TROPHY U-01 study has been activated,” he said.

TROPHY U-01 (ClinicalTrials.gov identifier NCT03547973) is an international, single-arm, open-label phase II study evaluating sacituzumab govitecan in a cohort of 100 patients with relapsed or refractory urothelial cancer treated with prior platinum therapy and an immune checkpoint inhibitor. A second cohort will include 40 platinum-ineligible patients previously treated with checkpoint inhibitor therapy. ■

DISCLOSURE: Dr. Tagawa is a consultant/advisor for AbbVie, Astellas Pharma, Bayer, Dendreon, Endocyte, Genentech, Immunomedics, Janssen, Karyopharm Therapeutics, Medivation, Sanofi, Tolmar, and QeD; has received institutional research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Aveo, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Dendreon, Endocyte, Exelixis, Genentech, Immunomedics, Inovio Pharmaceuticals, Janssen, Karyopharm Therapeutics, Lilly, Medivation, Merck, Millennium, NewLink Genetics, Novartis, Progenics, Rexahn Pharmaceuticals, Sanofi, and Stemcentrx; and has received travel and other expenses from Immunomedics, Sanofi, and Amgen.

REFERENCE

1. Tagawa ST, Faltas BM, Lam ET, et al: Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer: Results from a phase I/II study. 2019 Genitourinary Cancers Symposium. Abstract 354. Presented February 15, 2019.