Novel urothelial cancer Tx shows impressive response in phase II trial

The novel antibody-drug conjugate enfortumab vedotin produced an impressive 44% response rate in a phase II trial of urothelial cancer patients who had been treated with standard chemotherapy and a checkpoint inhibitor.

Researchers presented results of the study of 125 patients at the American Society of Clinical Oncology annual meeting in Chicago.

Twelve percent of bladder cancer patients studied had a complete response with no detectable sign of cancer. And 38% of patients whose cancer had metastasized to the liver responded to treatment, according to lead author Daniel P. Petrylak, MD, of Yale University, New Haven, CT.

This is the highest reported response rate in metastatic urothelial cancer to liver of any single agent or combination therapy to date, according to Dr. Petrylak.

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“This is an area that we know does not respond well to the checkpoint inhibitor therapy. What we’re also seeing, which is very interesting, is that there is no difference in response in those patients who have had programmed-death ligand-1 (PD-L1) progression or PD-L1 response. So [enfortumab vedotin] seems to work with responders and non-responders,” he said.

While the average overall survival was 11.7 months in the phase II trial, it’s too early to tell whether enfortumab vedotin improves survival in bladder cancer patients. The current phase III study is looking at survival, according to Dr. Petrylak.

Enfortumab vedotin could help to fill a need in the treatment of bladder cancer because outcomes from standard chemotherapy and immune checkpoint inhibitors fall short.

“About three-quarters of patients will not benefit from immune checkpoint therapy. So, there’s a need for third-line agents. In the past, we used single-agent chemotherapy for second line but really didn’t see great responses. At best, we saw 20% response rate and no improvement in survival,” Dr. Petrylak said.

Next:A "smart bomb" therapyDr. Petrylak calls enfortumab vedotin a “smart bomb” therapy because it targets Nectin-4, which is expressed in about 97% of bladder cancers. All the patients in the phase II trial expressed Nectin-4. The antibody to Nectin-4 is linked to a chemotherapy agent called monomethyl auristatin E (MMAE)-a similar agent to taxanes, according to Dr. Petrylak.

“Enfortumab vedotin will deliver MMAE directly to cancer cells as opposed to normal tissue, where there’s a much lower rate or no expression of Nectin-4,” he said.

Enfortumab vedotin is well tolerated, with 12% of patients in the trial discontinuing treatment because of adverse events. Side effects include neuropathy, neutropenia, and fatigue, according to Dr. Petrylak.

Dr. Petrylak, who did the phase I and II trials for the drug, says the phase II results were about the same as those in phase I. According to Dr. Petrylak , both the phase I and II results justify the application for accelerated approval for enfortumab vedotin in the treatment of bladder cancer. Researchers are conducting the international phase III trial comparing survival with enfortumab vedotin to standard chemotherapy in patients with metastatic urothelial that has progressed after chemotherapy and checkpoint therapy. A phase I trial is underway to examine the drug’s benefits for people who are newly diagnosed with advanced urothelial cancer but are ineligible for platinum chemotherapy. Another phase I trial is looking at treating advanced or metastatic disease by combining enfortumab vedotin with the checkpoint inhibitor pembrolizumab (Keytruda).

Also see: Deep-learning algorithm developed for bladder Ca detection

If enfortumab vedotin continues to show positive results in phase III trials, Dr. Petrylak said it will be integral in the armamentarium of bladder cancer treatment.

“I think back to 5 or 6 years ago when we really didn’t have anything for second-line patients. Now, we’re understanding more about the biology. We’re targeting different drugs to cancer cells. And again, I think patients who have metastases to the liver are a poor prognostic group, but now we’re starting to see ways of overcoming those challenges to treat these patients,” he said.

Seattle Genetics and Astellas Pharma are funding this research. The companies are co-developing enfortumab vedotin. Dr. Petrylak is a consultant/adviser for Astellas Pharma and has a received research funding from Astellas Medivation and Seattle Genetics. For full disclosures, click here.