I’m presenting the results from EV-103 cohort K. This is a randomised phase II cohort of a larger study looking at different combinations of agents with enfortumab vedotin. This study randomised patients 1:1 to EV monotherapy or EV plus pembrolizumab. The primary endpoint of the study was objective response rate with secondary endpoints of PFS, OS, duration of response and toxicity. 

The study was designed as a non-comparator phase II trial, not comparing the two regimens but really to explore the activity of the combination as well as the single agent to understand the contribution of components of pembrolizumab and enfortumab in the treatment of this advanced first-line cisplatin ineligible patient population. The treatment for these patients generally consists of gemcitabine and carboplatin chemotherapy, often followed by maintenance avelumab or immune checkpoint inhibition with single agent drug but not every patient qualifies for immunotherapy with gemcitabine and carboplatin as maintenance and most patients don’t qualify for single agent checkpoint inhibitors. So we need better first-line treatment for these patients and that’s the basis of the trial. 

The primary endpoint was objective response rate and was shown to be 64.5% in patients treated with enfortumab and pembrolizumab. The complete response rate was 10%. The median number of treatment cycles was 11. Enfortumab monotherapy the response rate was 45% with 4% complete response rate and the median number of cycles was 8. The responses were rapid, particularly in the EV pembrolizumab arm, and the median duration of response has not yet been reached for EV pembrolizumab and for EV monotherapy it was 13 months.

The progression free survival and overall survival remain immature but look promising and we hope to see those data evolve over time. The time to event endpoint for overall survival with EV was just over 22 months; EV monotherapy was 21 months. But when you look at the Kaplan-Meier curves you realise that those events are driven by just a few events at the tail end of the curve because the median follow-up is only 14.8 months at this time. So we expect that these numbers will change in terms of duration of response.

Toxicity with EV monotherapy was mostly as expected with skin reactions, fatigue, alopecia. For EV pembrolizumab combination therapy skin reactions were more frequent, that’s an overlapping toxicity of enfortumab and pembrolizumab. There was a low rate of pneumonitis seen which might be a toxicity common to both drugs, although still a relatively low rate. But otherwise there weren’t any new treatment emergent adverse events from the combination that you wouldn’t expect to see from either drug by itself.

So, in summary, this is a highly active combination with a potential to change how we treat first-line urothelial cancer. I’m very excited to see where this goes over the next several years.

EV-302 is the confirmatory randomised phase III trial that’s looking at EV pembrolizumab or chemotherapy in a broader population of first-line bladder patients, people who have regardless of cisplatin eligibility are eligible for the trial. So if you’re cisplatin eligible you would get gemcitabine cisplatin or EV pembrolizumab; if you’re cisplatin ineligible you would get gemcitabine carboplatin or EV pembrolizumab. That study will hopefully give us the definitive answer of whether or not EV pembrolizumab combination therapy has some substantial clinical benefit in patients in the first-line setting. 

To confirm the results, the combination may lead to an accelerated approval in the US but prior to the release of that data. There are also two muscle invasive studies, one in cisplatin eligible patients and the other in cisplatin ineligible patients. So it may move up even further in the course of the disease.