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Elizabeth Plimack: Hi, I'm Betsy Plimack. I'm a professor of GU medical oncology at Fox Chase Cancer Center in Philadelphia, and we are here at ASCO 2025. I'm pleased to be joined today by my colleague and friend, Shilpa Gupta, professor and director of GU medical oncology at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. Shilpa, welcome.

Shilpa Gupta: Thank you, Betsy, for having me.

Elizabeth Plimack: I really enjoyed your presentation today. So you spoke about the EVP (enfortumab vedotin plus pembrolizumab) data in EV-302, a study that was practice-changing when we saw it launch a couple of years ago. We all give a lot of EVP, but you looked at a special subset of patients in your presentation this morning. Tell us a little bit about why that subset was selected and what you found.

Shilpa Gupta: Yeah. So we wanted to see a lot of different things that patients who respond, we know that they have durable responses. But we wanted to tease out the data in terms of the number of cycles they received. Did they have more toxicity as compared to the overall population?

Because as you know, even though the protocol mandated that EV could continue indefinitely, that's really not a practical thing or a goal that we can achieve. So that was one of the goals. And of course, we wanted to see how these patients do long term and if there's a hope for cure for these patients at some point. So we took a deep dive into the CRs and the PRs and then focused on that for this presentation.

Elizabeth Plimack: I love that you said the word "cure." And you're not the only one to mention that in this room and in the forum this morning. So tell us about the CRs, the CR rate, the durability of those CRs, and what it might mean for us in terms of using that word "cure" with our patients.

Shilpa Gupta: So as you know, the overall response rates were 20% higher with the EV pembro over 65% compared to chemo. And the complete responders were twice as much in the chemo than the chemo arm. So it's 30% versus 15%. And not just the number of responders were higher, but the quality of responses was extraordinary.

Patients who did achieve a complete response as their best response had a 75% probability of being in CR at two years, and a 95% probability of being alive at two years. So that speaks volumes for these patients. And that begs the question of how much EV is actually needed.

And similarly, patients who achieve the best response as a partial response also had a 50% probability of being alive at two years. And those were higher than the chemotherapy subset, too. So that was really important to see for these patients.

Elizabeth Plimack: Right. Amazing. So let's talk a little bit about the number of cycles of EV. So the median number of cycles if I remember correctly was 12 or 13 for the PRs and CRs. The number of cycles of pembrolizumab was more, indicating that EV might have been stopped sooner than pembrolizumab.

Doing the math, a median of 13 cycles is about 10 months. So it seems like patients are stopping EV before pembro-- the responders-- stopping EV before pembro, and certainly stopping before that two-year mark where they're still in CR and still progression-free. What do you think we should make of that pattern? And how do we then use it when we talk to patients at the start of their EVP?

Shilpa Gupta: Right. No, that's a really great question, Betsy. And I think the reason that happens is because of the unique toxicities we see with EV, which are cumulative, like the peripheral motor and sensory neuropathy. And the more we give, the more we see that. And that's why patients who are responding got more treatments.

Despite those modifications and reductions, the efficacy was not impacted. So that was a really reassuring thing. But it is obvious that they got less EV than pembro because pembro did have an end date of two years. But still overall, if you count the EV and pembro, that also was less than two years in combination.

So I think what this tells us is that these toxicities will inevitably happen, like the neuropathy and the rash. But that does not mean that we have to keep going through those toxicities and pushing more EV if patients are responding and have had deep responses. Their efficacy will be maintained long term, as we've seen at least in the 2.5 year follow up data. So that's reassuring.

Elizabeth Plimack: So reassuring and so exciting that we're sitting here able to say that. I think if we go back, six years, 10 years in our careers, it's amazing that we can talk about treatment-free survival or stopping earlier, which is great. So with these new data and with what we already know about EVP, how do you counsel patients at two critical time points?

One, when you're first starting, and so you're talking about what's possible, not necessarily what's happened. And the second question is, what conversation do you have with those lucky 30% of patients who achieve a CR at that second confirmatory scan? And what do you suggest for them going forward?

Shilpa Gupta: Yeah. So with experience, discussions keep evolving. For example, my first patient who went on the study stayed on EV for three years, believe it or not, in CR from the first scan. And then eventually, we had to stop it. But not all patients are like that. That's probably an outlier.

So what I do is if a patient has achieved a CR consistently for a couple of scans, we talk about taking a break if they're beginning to get some neuropathy. And patients do get anxious about stopping a drug which is working. In fact, I'm sure you've seen that patients underreport their symptoms with EV pembro as opposed to chemotherapy.

So you really have to do a physical exam, take a good history, make sure they're walking OK. And then we take baby steps like, OK, if you're-- we'll take a break, do your next scan. If that's showing anything different or growing, we can always give you EV again. So we are having that kind of a discussion, and patients feel more and more confident.

And once I stop EV, in my experience, I have not really had to put a patient back on EV, except for maybe one patient where there was some recurrence after about 10 to 12 months in the same spot as before, which I resolved. And now she's got a few cycles and again been off for two years.

So I think we just have to get more confident that it is OK to take a break if patients are struggling with their side effects. And patients need to be told very clearly that if we keep forcing more EV doses, then they can become debilitated, and that's not a good thing.

Elizabeth Plimack: I think that's brilliant, and I think that's really great for our listeners to understand it's a new conversation for us. Everyone feels a little insecure stopping a drug that's working because historically, we've had to continue them to maintain the response. But we are in a new space, where I agree it is possible.

I'm with you. I haven't had to restart EV too many times. And when we do, we do still get responses. So sometimes you can think of it as a longer break. But learning how to have these conversations based on the confidence we've learned from the data you presented and from our experience I think is key.

Just in parting, how do you present EVP to the patients starting? You don't know if they'll respond or not. You hope they will. I think probably all of us used to start conversations with, "I'm so sorry we can't cure this, but our goal is to manage it as long as we can." Is anything changing in that conversation at the get-go for you?

Shilpa Gupta: I think that's really a great question, Betsy. And I always am very optimistic when offering EV pembro. But unfortunately, not all the patients follow the majority of the data. And I've recently had some patients who, unfortunately, are resistant or primary resistance to the combination, and they blow through at the first scan.

So we have to be just be cautiously optimistic. And I say, well, chances are that you will respond. And if you respond. That will be maintained. And the first scan is what will show us because as you know, the responses are seen early on. So that becomes our first assessment point where we know if we are going in the right direction or not.

Elizabeth Plimack: I like that. I like that. Yeah, setting the expectation around the conversation to have at the first scan. That's great. Well, Shilpa, thank you. I think the data you presented are amazing, very impactful, very practice-reaffirming and confirming. And I think the way you just sort of shared with our listeners how to now have these conversations in this new era is going to be really helpful.

Shilpa Gupta: And thanks, Betsy. I want to compliment you on trying to address the question that's on everybody's mind about the de-escalation of treatment. So I hope to--

Elizabeth Plimack: Yeah, we're trying to call it induction and maintenance to give people that confidence that we're inducing a response and then hopefully maintaining it. But yeah, patients are eager to enroll in a study that has a finite amount of cytotoxic.

Shilpa Gupta: Absolutely.

Elizabeth Plimack: And I'm glad that they trust us with this study, so hopefully, we'll have data to present. Yeah.

Shilpa Gupta: Thank you.

Elizabeth Plimack: Thank you.