Thomas Powles, MD, MBBS, MRCP, from Barts Cancer Centre, shares insights from the EV-302/KEYNOTE-A39 trial and its implications for the future of enfortumab vedotin and pembrolizumab (EV+P) combination therapy for urothelial carcinoma.
Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology and director, Barts Cancer Centre at St. Bartholomew's Hospital, details exciting findings from the EV-302/KEYNOTE-A39 trial that suggest a new standard-of-care treatment approach is coming in the realm of urothelial carcinoma.
This transcript has been lightly edited for clarity.
How does the combination therapy of enfortumab vedotin and pembrolizumab [EV+P] fit into the treatment paradigm for urothelial carcinoma, and how is it addressing an unmet need for patients?
So the first thing to say is metastatic urothelial cancer, also known as bladder cancer is associated with 200,000 deaths globally every year. And the average life expectancy of these patients is about 1 year. So it's a really high area of unmet need. It’s one of the top 10 most common cancers and the treatment hasn't changed for 40 years—it's been platinum-based chemotherapy.
Immune checkpoint inhibitors, one of which is pembrolizumab, have been developed over the last 5 to 10 years. And it's shown single-agent activity. But it's never been strong enough to beat chemotherapy by itself. Enfortumab vedotinis an antibody drug conjugate. It targets nectin-4, and about 98% of patients with urothelial cancer express nectin-4. It was tested in patients, initially, whose cancer had progressed after that initial chemotherapy.
Essentially, it was a second-line therapy. A trial took place in the United States combining enfortumab vedotin with pembrolizumab and they showed unusually good results. And instead of that overall survival being about 1 year, they showed, in a small trial, overall survival was 2 years. Now there's a scientific rationale for combining these drugs together in that it looks like chemotherapy—when you combine with immunotherapy—is antagonistic: the 2 do not work well together. But it looks like when you combine enfortumab vedotin with pembrolizumab, the 2 are additive.
So, we as a group and a big team of people, 200 sites globally, many countries, thousands of investigators and about 900 patients, took part in a trial to confirm whether or not we can beat standard chemotherapy—gemcitabine cisplatin, gemcitabine carboplatin—with this new promising combination of enfortumab vedotin and pembrolizumab.
What results would you like to highlight and what are their implications for the treatment of urothelial carcinoma going forward?
The findings of the trial, it was a big, randomized phase 3 study. We are confident in the results of the trial. We showed a big reduction in the time for the cancer to grow or die—that's progression free survival—of 55%. And that is a huge extension which extends progression free survival before from about 6 months to 12 months now. So a doubling in progression free survival. We also showed a 53% reduction in the risk of death. We've never done a study before in urothelial cancer where chemotherapy has been beaten.
The 53% reduction in risk of death is unprecedented from a urothelial cancer perspective. We've done many previous trials, we've sometimes had 15% reductions in death, sometimes 20% reductions in death—not statistically significant. But this is the first time we've achieved that major goal. And that's seen as a major breakthrough and it will result in chemotherapy in the United States no longer being used as the standard of care, but enfortumab vedotin and pembrolizumab being used.