Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I have the opportunity to speak with Dr. Jonathan Rosenberg of Memorial Sloan Kettering. Thank you so much for talking with me.

Jonathan Rosenberg: My pleasure. It's good to be here.

Alicia Morgans: It's wonderful to talk to you and really exciting to hear about the updated results from EV-301, which you presented during the meeting. Can you tell us a little bit about the EV-301 study and really just set the stage for the trial design?

Jonathan Rosenberg: EV-301 was a randomized, Phase III trial that enrolled patients with metastatic urothelial cancer who had progressed on a platinum chemotherapy regimen as well as a checkpoint inhibitor. And patients were randomized one-to-one to enfortumab vedotin or to standard salvage chemotherapy, I hate the term salvage chemotherapy, but that's what it was kind of called, docetaxel, paclitaxel, or vinflunine in this study read out at the first interim analysis, which essentially then became the final analysis because of the positive results with a hazard ratio of 0.0 with an improvement of about four months in median survival. The updated data essentially confirms all the original data with perhaps a bit of a plateau on the curve far out at two years and beyond, with about a 10% improvement in two-year survival for patients treated with EV at almost 30%, which in the third-line setting, although not where we want it to be, is still quite impressive and 10% higher than in patients who receive chemotherapy. And so since that time, it's become a standard of care, if not the standard of care, in platinum and checkpoint refractory patients.

Alicia Morgans: And it's been so important, I think, as you said to be that opportunity for patients to not get one of those single-agent chemos that we use in that setting. And with this updated analysis, how does this affect your practice?

Jonathan Rosenberg: Well, I think it gives me the ability to talk to patients about long-term outcomes in advanced disease, where we really unfortunately still have relatively low numbers of patients making it to five years. And so we now are seeing patients who in the third-line setting are living at least two years, even though it's clearly not the median. The median's around 13 months with enfortumab.

It also confirms the toxicity profile of the drug and really there weren't late significant toxicities. There were a few more rashes, I think three rashes that were identified late, which reinforces the fact that the skin toxicity from enfortumab tends to occur early and the very severe toxicity, which can occur in about 1% of patients or less, occurs within the first month usually. And so it's an early event in the course of the disease and the late effects in terms of toxicity are as predicted. Neuropathy, of course, is a cumulative toxicity for some patients. And there was some increase in neuropathy, although patients who experienced severe neuropathy stopped treatment, unfortunately. And so those two toxicities along with hyperglycemia do remain the sort of unique features of the drug.

Alicia Morgans: So thank you for going through that. I think one of the important things that I would consider as I use EV or enfortumab vedotin in my practice and really think about this data is what proportion of patients remain on EV as it's initially dosed, so three on one off, at that to your time point or farther out? Does this study speak to that at all? What proportion of patients are still on therapy?

Jonathan Rosenberg: About 12% of patients are still on therapy, so a very small number, which also suggests that there's some durability to some of the responses, even if patients are off therapy. I think in practice people are modifying doses. People are modifying schedule in order to maintain people on drug. My experience has been sometimes that you can actually stop this agent for months without patients progressing while they recover from toxicities. Usually, those are in people who are responding to therapy and have a nice partial response or even a complete response.

And so we can, I think, feel comfortable that we might take a pause on therapies for patients with significant peripheral neuropathy. The neuropathy does get better as time goes on. And I often find that patients respond well to physical therapy to particularly deal with the motor and sensory neuropathy that occurs. It's not simply paresthesias, but you can get numbness and even muscle weakness in more serious cases. And so also early evaluations by neurology can be very helpful.

Alicia Morgans: I think that's really, really useful. So thank you for going through that very, very practical guidance. So what would your message be to clinicians who are trying to think about this and really talk to patients, integrate enfortumab vedotin in this line, or in other lines? Where do you place this data and where do you see enfortumab vedotin going in the future?

Jonathan Rosenberg: I think it's very nice to have an agent that you know has a high response rate, about 40% in the Phase III trial, 44% in the Phase II trial. That in patients who are highly symptomatic, who need a response, you can actually reach for this drug and feel very comfortable with it. I am using it in second line in certain patients, post either platinum or post checkpoint, depending on their initial characteristics, based on the disease characteristics. It appears to be more active than other agents, including immunotherapy, in patients with liver metastases or bone metastases and often can have substantial palliative benefits for patients with painful bone metastases. And so there are certainly a role with earlier treatment.

We are going to see at some point in the next year the results of EV-103, which is a multi-cohort study looking at different combinations of enfortumab with other agents. And EV-103 Cohort K at some point will give us results of EV monotherapy in untreated patients and enfortumab and pembrolizumab as combination therapy in untreated patients as well. And so that randomized cohort will give us a sense of the future role of enfortumab as first line therapy for advanced urothelial cancer. The Cohort A of that study was reported several years ago, which showed a 73% response rate in the first line setting when combined with pembrolizumab. And so we're very excited about this.

There are Phase III trials ongoing with this regimen and EV-103 Cohort K when it reports will give us a sense of what's the contribution of enfortumab and how much does pembrolizumab add to that. And I think both are interesting questions because we see enfortumab in the second line with a 50% response rate, 40% in the third line. What is enfortumab monotherapy in the first line? Is it 60%? Is it 55%? If it's 60% and EV-pembro is 73% than that time to event endpoints become much more important. And so we'll see those data at a meeting in the future, I'm sure.

Alicia Morgans: Well, there's a lot to look forward to and we already have a lot of opportunity with this particular agent. Thank you so much for sharing these updated results and your perspectives on the use of enfortumab-vedotin in urothelial carcinoma.

Jonathan Rosenberg: Thank you so much.