GU Cancers 2019 | Sacituzumab govitecan in patients with previously treated mUC

Sacituzumab govitecan is an antibody-drug conjugate. The target of the antibody is called Trop-2. Trop-2 is a cell surface antigen that’s present on the majority of epithelial tumors. That includes urothelial carcinoma, where it’s over-expressed particularly in invasive urothelial carcinomas. The study started off as dose escalation Phase I basket study, with a number of different tumor types that included urothelial carcinoma. In that Phase I portion of the study, which is now published, it was determined that myelosuppression was the dose limiting toxicity, and the recommended Phase II dose was 10 milligrams per kilogram, given on a day 1 to 8 Q21 day schedule. There was an early signal of activity in urothelial carcinoma patients, which has been published, so we performed a Phase II expansion study. We enrolled 45 patients with advanced treatment refractory urothelial carcinoma. They had measurable disease and an ECOG performance status of 0-1. The primary endpoint of the study was objective response rate, measured by RECIST 1.1. We also looked at duration of response, progression-free survival, and overall survival, as well as tolerability and adverse events.

The 45 patients that were enrolled received a median of two prior lines of therapy, A subset of them also received immune checkpoint inhibitors. The study went over a number of years. It was only open for about 7 weeks post the approval of the first immune checkpoint inhibitor in the United States, so it was only a subset that received that. For the heavily pre-treated patient population, that was about three quarters with visceral disease, a third that have liver metastasis, overall I would say that it looked good. The objective response rate was confirmed at 31.1%, which was maintained more or less amongst the different subsets. That was at the cost of some moderate toxicity, but not a lot of high grade toxicity. So the only grade three to four toxicities that happened in at least 10% of patients were laboratory toxicities. There was 9% instance of diarrhea and fatigue at a grade three level. There were also grade one and grade two. There was 38% grade three and grade four neutropenia, but only 7% had febrile neutropenia.

5 patients came off for potentially drug-related toxicity, but none were due to neutropenia. There were no treatment-related deaths. In the setting of a treatment refractory patient population, the objective response rate is pretty impressive, compared to historical controls. Those that responded had a duration of response of a median of 12.9 months. So most of the patients that responded had a response that lasted more than a year, and also, they were able to tolerate drug for more than a year. The onset of response was most often at the first scan. The median time to onset of response was 1.9 months. A few patients responded later, including one that responded after 7 months. For the overall population, those that responded as well as those that didn’t respond, the median progression-free survival was over 7 months, with an overall survival over 16 months. Again, both overall, compared to historical controls, because this was not a randomized study, was pretty impressive. The combination of what we see in terms of efficacy, as well as the tolerability, is very promising. This led us to launch a larger, more confirmatory study, called the TROPHY U-01 study. That study has been activated, we are still opening new sites, and although it’s still relatively early, it is anticipated that we are going to finish enrollment hopefully by the end of the year.

The primary cohort that we’ll be looking at is 100 evaluable patients that have metastatic urothelial carcinoma and progression, despite platinum-based chemotherapy, and a PD-1 or PD-L1 immune checkpoint inhibitor, with no limit of lines of therapy. Again, we are looking at the objective response rate, as well as tolerability. There will be an exploratory cohort looking at patients that are cisplatin ineligible, that have also had cancer progression despite prior immune checkpoint inhibitors.