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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Bradley McGregor, who is the Clinical Director of the Lank Center for GU Oncology at Dana-Farber, and of course, a GU Medical Oncologist. Thank you so much for being here with me today, Dr. McGregor.

Bradley McGregor: Thanks so much for having me.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about enfortumab vedotin, and specifically dig into a presentation that you have presented at ASCO 2021 on some updated data from cohort two from EV-201. But before we get to that, can you explain to everyone just a very brief rundown, what is enfortumab vedotin, because this is really in a new class of medications for GU medical oncology?

Bradley McGregor: Yeah. I think enfortumab vedotin, along with sacituzumab govitecan, has really revolutionized the treatment of [inaudible 00:00:58] CR carcinoma. For the longest time, we had platinum-based therapy, and following that there was really nothing that was efficacious. Then we had the advent of immunotherapy, which showed us some viable benefits. And beyond that, cytotoxic chemotherapy has a 10% to 15% response rate at best. And now we have two antibody-drug conjugates that show efficacy following immune checkpoint blockade.

Enfortumab vedotin was the first one that was developed, and we had the initial phase 2 trial looking at enfortumab vedotin following immunotherapy and platinum-based chemotherapy. So, enfortumab vedotin is an antibody-drug conjugate against nectin-4 conjugate to MMAE. Nectin-4 is universally expressed on urothelial carcinoma, so this is not a marker you need to check for in the clinic or as a pathologist. This is something that can be given to all patients with urothelial carcinoma.

So in the initial phase to try out post-IO and post-platinum, we saw a response rate of over 40%. That led to its FDA approval, and subsequently had a phase 3 trial in that setting of post-IO, post-platinum of enfortumab vedotin versus dealer's choice of chemotherapy, generally different taxanes, which showed an overall survival benefit in that setting. So, certainly, this is a very active drug and is now a regular part of my clinical practice.

But for those patients who are not eligible for platinum-based therapy and who got immune checkpoint blockade alone, the data wasn't as clear. In the initial EV-201, there are two cohorts, those that had received platinum immune checkpoint blockade, and those that had received immune checkpoint blockade alone. So, we have previously seen results of the cohort two presented earlier this year of looking at those patients who were status post-immune checkpoint blockade and ineligible cisplatin therapy, hadn't received any platinum at all, and they showed a 52% objective response rate with a 20% complete response rate and mean duration of response of near 11 months.

So, at ASCO this year, we presented an updated analysis with an additional 3 months of follow-up. So again, this cohort is taking those patients who received immune checkpoint blockade in the metastatic setting and were ineligible for platinum chemotherapy. And that was just going to be due to impaired renal function, creatinine clearance less than 60 but over 30, hearing loss, or even a performance status over 2.

And so we looked at the population that received this regimen in this setting, and I think it looks very similar to what you are going to see in your clinic. 70% of these patients had a decreased GFR, less than 60, 15% had a BMI of greater than 30, 12% actually had a PS of 2, and 80% of these patients had visceral disease.  Likely due to the nature of the design of looking at those patients who are cisplatin-ineligible, there was actually a higher component of upper tract disease in this cohort, likely due to the effects of the nephrectomy on renal function.

So getting right down to the data. With the additional 3 months of follow-up, we see that the objective response rate holds at 51%, with a confirmed complete response rate actually increasing to 22%, and progressive disease as the best response was only seen in 10% of the patients. And with this extended follow-up, we see the median overall survival was 16 months, and the median duration of response was close to 14 months. So, this is certainly a very active agent, and this data shows that it is active independent of the receipt of prior platinum or not.

Alicia Morgans: So a couple of things I want to emphasize and also ask about because that is really impressive data, but just to clarify for everyone, these patients are cisplatin-ineligible, and really were only getting IO checkpoint as their front-line. And if they are cisplatin-ineligible, I would imagine that many of these patients, if they are getting IO and front-line, are probably also carboplatin-ineligible.

So, this patient population is the population that we see every day. These patients are on the fence, who might have that borderline performance status, may have renal function issues that don't make them eligible, or may even just feel like, "You know what, I don't have the support I need at home. I don't have the wherewithal to take chemotherapy." And there are patients who, for many reasons, can't take chemotherapy, particularly cisplatin. So, having an option for them, even when their PS is 2, I think is exceedingly meaningful, and so I'm really glad that we have this updated data and have this as a potential consideration for these patients.

The other thing that I really want to dig into though, is that sometimes the side effect profile, even if the drug is effective, the side effect profile can make it really difficult for patients to actually get the drug. In this case, it sounds like, actually, the median duration of response was quite long, so I'm assuming patients were getting the drug. What was the AE profile or the side effect profile that you found in this extended follow-up?

Bradley McGregor: Yeah, so I think that's a great point. To your point as well, the median age of patients in this trial was 75, so these are really elderly patients with comorbidities that were able to tolerate this drug for quite some time. And when we look at the tolerability, there are really no new adverse event signals based on what we saw in cohort one or even the phase 3 trial.

So, overall close to 100% experienced any sort of treatment-related adverse events, 55% had a grade 3 or higher. We know, from the phase 2 and phase 3 data and other trials, that the events of special interests are going to be neuropathy, hyperglycemia. We didn't really [inaudible 00:06:44] . We didn't see anything unique in that regard. Comparable to what we've seen in other trials, fatigue, decreased appetite, were the most very common side effects. Neuropathy, we saw it in grade 1 or 2, neuropathy in 50% of the patients, but only 3% actually had grade 3 or higher. And so, overall, I think really well-tolerated regimen, with no new safety signals.

I will point out that there were four treatment-related deaths in this analysis. This has been reported previously. So, no new treatment-related deaths were seen with extended follow-up. These patients had a higher BMI and we've seen a few different comorbidities, so it does highlight the importance of even with a drug, such as enfortumab vedotin, with this targeted therapy, you still have to be monitoring patients closely and really thinking cautiously about your treatment decisions.

Alicia Morgans: Yeah, I absolutely agree. And although this drug may be more tolerable and maybe something we can give to some patients with borderline performance status, this is still a drug that's treating cancer, and so we absolutely need to keep a close eye on these patients, consider things like dose reductions or certainly monitoring weekly when those patients come in, especially if you are new to using this drug. I think that's an important part of getting a sense of how to ensure that you recognize and then react to any side effects that do occur.

So, when you use this drug in the clinic, how have you found it? Are your patients tolerating it? Is your real-world experience similar to what you are reporting in this abstract?

Bradley McGregor: Yeah, so we look at the dosing of EV, it is given at 1.25 mg/kg, day 1, 8, and 15 of a 28-day cycle. So, the patients are coming to the clinic 3 out of 4 weeks. And I think that can be challenging for the patient as you go on this on an extended basis. I generally found, though, that I'm able to get patients to do 3 to 4 months with that dosing schema reasonably well. I'm not afraid to hold doses. As an investigator in the trial or in clinical practice, I've held doses for 2 weeks or even a month, and been able to still see and maintain response. So I do, especially in patients, such as this, I have a low threshold just to skip a dose, let a patient recover, because I am really trying to maintain that dose intensity over the long term.

Once I get into 4 months, 5 months of therapy, I do find it a challenge to keep that. I very frequently will get dose reductions down to 1 mg or even at 0.7 mg/kg, and I'll often look at dosing schedules where I may have to omit a day-15 dose here or there. But I think it is well-tolerated. The long-term is a question. And I think the trial design says you give the drug indefinitely, so I will try to get the drug as long as possible, but especially after those first 4 months, I may start dropping doses just to improve tolerability and keep patients on a longer-term.

Alicia Morgans: Well, thank you for those real-world insights. It is so important as we try to use these drugs in our clinic. And thank you, of course, for updating us on ASCO 2021. Very exciting. Another virtual meeting. Hopefully, we'll be in person at some point in the future, but when we can't be, we appreciate you sharing all of your insights on UroToday. Thank you for your time, Dr. McGregor.

Bradley McGregor: Thank you.