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Alicia Morgans: Hi, I'm so excited to be here with Dr. Jonathan Rosenberg, who is the chief of the Genital Urinary Oncology Service at Memorial Sloan Kettering. Thank you so much for being here with me today.

Jonathan Rosenberg: My pleasure. It's a great to be here today.

Alicia Morgans: Wonderful. So, Jonathan, you know, you've been really involved with Enfortumab vedotin and pembrolizumab as a combination and of course, independently as well for urothelial carcinoma, and there was a recent approval for this combination for that disease. Can you tell me a little bit about the approval and the evidence that led to the approval?

Jonathan Rosenberg: So, Enfortumab and Pembrolizumab were approved just about six, seven weeks ago based on EV103, cohort K, which was a randomized cohort of EV pembro compared to EV monotherapy, and showed that the response rate was 64.5% with EV pembro and 45% with EV monotherapy. The time to event endpoints are immature, but are promising with median overall survival of over 20 months which is a lot higher than we might expect in a cisplatin eligible population. And this led to the FDA approval and the label combined both cohort A, which was the initial cohort plus cohort K, giving an overall response rate of 68% in patients with metastatic disease. And so this data appears dramatically better than what we might have expected historically with gemcitabine and carboplatin which in the only randomized phase through trailhead intermediates arrival of nine months compared to 25 months with EV pembro and cohort A. And so at ASCO this year, we're gonna see updated data from both cohort K and cohort A, including four year outcomes from EV pembro cohort A which really are very promising in terms of long-term survival.

Alicia Morgans: Well, let's take a moment and, and think about that four year outcomes for patients with metastatic urothelial carcinoma. Any comments?

Jonathan Rosenberg: Well, I think we haven't seen that before. This is a sea change dramatically, I think it bodes well for the future of patients with the disease. You know, we're seeing survival in the 30, 40% range at four years. We'll see next year what the medians, five year survival will be. But very exciting. We expect five to 10% of patients alive at five years in historical with platinum-based chemotherapy. And so I think we are entering a new age where we're expecting now a very good median survival for patients with metastatic urothelial cancers.

Alicia Morgans: Well, it's, it's certainly phenomenal to hear that and, and, and something that, as you said, see change which is so important for patients now, as clinicians are starting to use this combination for their metastatic patients in clinic, I think that as, as we talked about, there are things for them to be excited about, obviously the response rates, but also things for them to know how to manage. So when they're thinking about EV and Pembro as a combination, what advice would you have for them in terms of monitoring in terms of some of the most common side effects that they may have to be on the lookout for?

Jonathan Rosenberg: There are, I do, I think of con the side effects in two categories, the early potentially severe side effects and the more chronic long-term side effects. On the early potentially severe side effects you have to watch out for severe hyperglycemia. It's a very, very tiny fraction of patients, although a larger group of patients have more mild hyperglycemia that needs to be monitored. And skin reactions, which occasionally can be life-threatening or fatal. And there is a black box warning around TEN, I think those patients tend to get that toxicity, that severe toxicity in the first month or two of therapy. And I encourage clinicians to see patients at each visit while they're getting treatment because you can identify some of these things early and deal with rashes and abort treatment for the week or dose reduced going forward. But if you haven't seen the patient, you really don't know what's going on. You don't, they, you haven't looked at their back at their legs, at their arms, at their armpits and their mouth to see what's happening because many of these toxicities can be ameliorated if identified early.

Alicia Morgans: Absolutely. And especially those painful rashes that might be in the eyes, the mouth, these are definitely warning signs,

Jonathan Rosenberg: Right? They're red alarms that you should be sending a patient to a dermatologist holding treatment. The skin itself we see both pembrolizumab toxicity, which is inflammatory rashes as well as direct toxicity from Enfortumab vedotin because nectin-4 is expressed in the skin low levels in many, in, everyone and variable levels, probably between patients. And so the direct chemo effect in the skin can cause the blistering rashes that probably lead to TEN or other things. And so if those are found early and treatment is stopped, you might have a hope of minimizing and reducing the chance of something more serious happening for the patient.

Alicia Morgans: Great. So monitoring, so important, and as we think of the longer term toxicities, neuropathy comes to mind, at least in my clinical practice, as something that I need to be very aware of and sometimes make dose adjustments, dose reductions, change the schedule somewhat, sometimes even hold EV, can you tell me a little bit about how you think about neuropathy with this combination?

Jonathan Rosenberg: Neuropathy, unfortunately is often the price of success of the combination in that patients need to be on it for a reasonable amount of time, which means it's working. And so you have to manage the chronic toxicity in someone who's benefiting from the drug. And so I tend to employ dose holds as a first step. And often mild neuropathy will improve over the few weeks. But as time goes on, it can become more severe and require dose reductions. And it's not just a sensory neuropathy, it's also a motor or proprioceptive neuropathy. And for those patients, actually physical therapy can be very important at maintaining or even restoring function. And it's also important to remember that there are patients who have a good response to Enfortumab who can stop and who can wait. And I have for example one patient who's been off now for almost 18 months without recurrence of her cancer for metastatic platinum refractory PD-L1 refractory disease. Another patient who was originally on the phase one, has been off for two years almost now without any evidence of cancer progression. And so this is a drug that has long lasting effects in a positive way for these cancer patients. And so patients who are responding should be reassured that a dose hold or a dose reduction is not likely to cause any short term harm to them and might allow them to continue on therapy or resume it later on if they need it.

Alicia Morgans: Absolutely. I think you're not alone in seeing those long-term responses despite therapy holds. And I think that that's one of the unique things about this particular agent. And, and maybe more akin to its chemotherapy kind of history almost, you know, being that it does have this MME on there and we in the past would give chemotherapy and then break, and, and so we have seen responses, nothing like the ones that I've seen with EV though, which is, which is really interesting. When you do that, do you continue the pembrolizumab? Do you hold the pembrolizumab? How do you think about that?

Jonathan Rosenberg: I tend to give the pembrolizumab up to two years and then stop. And we, I have not had any patients on EV pembro that have gotten that far and able to be on therapy. And so people that I've had have been observed at that point because of neuropathy, for example. And so I usually maintain the pembrolizumab if the Enfortumab has to stop, but I usually stop the pembrolizumab at two years as we do with most metastatic urothelial cancer patients. I think it's very interesting though that MMAE may have immune effects that we really don't yet totally understand. And there's data from CGEN that was reported actually at SITC I believe last year, showing that you really do generate immunogenic cell death and an immune response with Enfortumab monotherapy. And presumably it's being augmented by pembrolizumab such that there's probably more than additive activity here. But we'll see what the phase three trial shows. EV302 is fully accrued. Hopefully we'll see those results in the next year or two and really learn whether this is going to change the standard of care permanently for urothelial cancers.

Alicia Morgans: It's just always exciting to have these conversations. So as you think about this, as you sort of wrap things up, can you briefly just comment on the schedule for the drugs, because this is a little different than EV monotherapy. And then tell me what are your thoughts for the future and what would your message be on this approval?

Jonathan Rosenberg: So Enfortumab on the frontline schedule is day one and eight every 21 days instead of day one and eight and 15 every 28 days. And pembrolizumab is day one, and the schedules were aligned such that it just was easier for patients. The dose, the dosing of Enfortumab is not particularly different in terms of total dose over time, although slightly less. But if you need to delay, it's fine. And do day one, day eight and wait until day 28 to give the next cycle. I don't think there's any real concerns there. I think this approval is a landmark in the treatment of advanced bladder cancer and we'll be hopefully seeing long-term survival in a chunk of patients much bigger than before, but not everyone responds and still the majority of the patients will eventually progress as time goes on. And so we need treatments beyond this, and we have other antibody drug conjugates, we have other targeted therapies. And we really now need to understand how well they work post and, and pembrolizumab. Can we rejuvenate an immune response with other agents beyond PD-1, PD-L1 inhibitors? Can we use FGFR3 inhibitors more effectively? Are there other targeted therapies that are going to be very useful in this patient population and how well the other ADCs really work in the post EV space, because that data's not really out there yet.

Alicia Morgans: Well, I think with every advance we come up with 20 more questions at a minimum which le leaves us with a lot to do, but a lot to celebrate. Yes, exactly. So thank you so much for your time and your expertise.

Jonathan Rosenberg: My pleasure.