Novel Agent Shows Promise in Advanced 'Post-Checkpoint' Bladder Cancer

SAN FRANCISCO — A novel antibody drug conjugate showed activity in patients with metastatic urothelial cancer, including those who had progressed with checkpoint inhibitors, a new phase 1/2 study reports.

Treatment with investigational agent sacituzumab govitecan (Immunomedics) induced an objective response rate (ORR) of 31.1% in the overall cohort of 45 patients. Within this group, 17 patients had been previously treated with checkpoint inhibitors, and four patients within this subset (23.5%) also responded.

The ORR was 33.3% among patients with liver metastases (5/15).

"Among patient subsets, which are admittedly small, there appears to be a response despite liver metastasis or prior immunotherapy," said lead author Scott Tagawa, MD, associate professor of clinical urology at Weill Cornell Medical College, New York City.

"This is in the setting of reasonable drug tolerance," explained Tagawa. "There was a relatively low rate of discontinuation due to adverse events, none due to neutropenia, and there were no treatment-related deaths."

The study results were presented here at the Genitourinary Cancers Symposium (GUCS) 2019.

Advances in treatments for bladder cancer had been limited for the past several decades, explained Matthew Milowsky, MD, section chief, genitourinary oncology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill. "But that was until the development of immune checkpoint inhibitors, with the Food and Drug Administration approval of five agents between May 2016 and May 2017."

Milowsky, who served as a discussant for the paper, noted that with the advent of these agents, survival has improved compared with historical controls.

We've created a new clinical disease state, namely the post immune checkpoint inhibitor space. Matthew Milowsky, MD

However, only a limited number of patients actually derive benefit from immune checkpoint inhibitors.

"When you look at the response rates for patients with platinum-resistant metastatic urothelial cancers, you'll see that they range from 15% to 30%," said Milowsky. "Although these agents are extremely effective, they do not benefit the majority of patients."

Thus, additional agents are desperately needed because most patients do not respond to immunotherapy. "In having the success with immune checkpoint inhibitors, we've created a new clinical disease state, namely the post immune checkpoint inhibitor space," he added.

Promising Response Rate

Tagawa and colleagues conducted a phase 1/2 basket study to investigate the activity of sacituzumab govitecan, a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the most active metabolite of the chemotherapeutic drug irinotecan.

"Trop-2 is an epithelial cell surface antigen that is highly expressed in urothelial cancer and is overexpressed particularly in invasive tumors," explained Tagawa.

In the first dose-escalation phase, patients were enrolled who had a variety of treatment-refractory advanced epithelial malignancies and were unselected for Trop-2 expression.

Based on the phase 1 results, the recommended phase 2 dosage was 10 mg/kg given on days 1 and 8 every 21 days. Tagawa noted that the efficacy signal "looked interesting" in the subset of patients with advanced urothelial carcinoma, so the phase 2 expansion cohort included 45 patients with urothelial cancer.

Patients' median age was 67 years and they had received an average of two (range, 1-6) prior treatment lines, which included platinum-based chemotherapy (95%) and immune checkpoint inhibitors (38%). In addition, 33 patients had visceral metastases involving the liver (n = 15), lung (n = 27), and other organs (n = 5).

The median duration of follow-up was 15.7 months, with a median eight treatment cycles and relative dose intensity of 95.2%. At the time of data cutoff, five patients remained on treatment, and of this subset, three had an ongoing response.

A total of 14 patients (31%) achieved an ORR, with two complete and 12 partial responses. Among patients with visceral involvement, the ORR was 27% (9/33).

"Most patients who responded did so early, at about 1.9 months," explained Tagawa, although some did so later, at up to 7 months. The median duration of response was 12.9 months, and three patients had response durations of 17+, 19+ and 29+ months at data cutoff.

Mean progression-free survival was 7.3 months and overall survival was 18.9 months.

As for treatment-related adverse events, Tagawa pointed out that the safety profile of the drug was consistent with prior reports and the rate of treatment discontinuation because of side effects was relatively low.

Just five patients stopped treatment because of adverse events, none because of neutropenia, and there were no treatment-related deaths. "The grade 3 and 4 adverse events were largely restricted to laboratory-based events," he said, including neutropenia and anemia. Other adverse events included hypophosphatemia, diarrhea, fatigue, and febrile neutropenia.

Further Study

"Sacituzumab is a new exciting agent potentially for patients with metastatic urothelial cancer, including in the post checkpoint inhibitor space as well as in patients with visceral metastatic disease," commented Milowsky. "Toxicity is manageable but may be limiting in select patients, and the toxicity profile of diarrhea and myelosuppression predominantly may be useful to select among several new agents, including in the post checkpoint inhibitor setting."

Sacituzumab govitecan also has shown clinical activity in metastatic triple-negative breast cancer, as reported this week by Medscape Medical News.

Tagawa noted that continuing research in bladder cancer is in the works. "We believe that 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 is an international, single-arm, open-label phase 2 study that will evaluate the agent in patients who have progressed on platinum-based therapy or immune checkpoint inhibitors.

There will also be a second cohort comprised of patients who were deemed unfit for prior platinum-based therapy and progressed after immune checkpoint therapy.

The study was funding by Immunomedics. Tagawa has disclosed financial relationships with AbbVie, Astellas Pharma, Bayer, Dendreon, Endocyte, Genentech, Immunomedics, Janssen, Karyopharm Therapeutics, Medivation, Sanofi, and Tolmar. Several coauthors have disclosed multiple financial relationships with industry.

Genitourinary Cancers Symposium 2019. Presented February 15, 2019. Abstract 354

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