Elizabeth Plimack: Hi. We're here at ASCO 2025. I'm Betsy Plimack. I'm a genitourinary medical oncologist at Fox Chase Cancer Center. And I'm here today with Jackie Brown, who's an assistant professor of Medical Oncology at Winship Cancer Institute at Emory in Atlanta.

Jackie, you gave a really amazing discussion today—

Jacqueline Brown: Thank you, Betsy.

Elizabeth Plimack: --discussing three really interesting oral abstracts in urothelial cancer. We're really eager to share your thoughts with our audience. Let me just ask you to quickly, if you can, go through the three studies that you talked about, just in a nutshell. And then let's take a deep dive into each one and the questions they pose to us in practice.

Jacqueline Brown: Perfect. So starting from the top. So there were three great abstracts. And I should say, the credit for any good discussion is that it was great data to be able to talk about.

Our first study was the JAVELIN Bladder Medley. And there are multiple arms of this. But the arm that Dr. Hoffman, since it's discussed today, was the sacituzumab govitecan-containing arm. And essentially, it's a relatively complex statistical design that I'll spare everyone in this moment. But these were patients who received platinum doublet chemotherapy and would have that indication for maintenance avelumab, stable disease or better, and received either maintenance avelumab or maintenance avelumab plus sacituzumab govitecan in this maintenance setting.

And we ultimately saw an improvement in progression-free survival, hazard ratio of 0.49 that was significant, no significant difference in overall survival interim analysis, difference in response rate, and a pretty expected toxicity profile for SG added to avelumab.

Elizabeth Plimack: You said something really fascinating. It was a perfect way to phrase it, that we have a complicated relationship with sacituzumab govitecan. Indeed, it's something we leaned on a lot when it was first approved. There's experience in breast cancer. Urothelial cancer, we learned, is different. What do you think about the addition of SG in that specific maintenance phase?

Jacqueline Brown: Yeah. What we can take away from JAVELIN Bladder Medley is the concept, because I think it was an appropriate structure for a trial designed at that time, but we've moved on from the induction-therapy, maintenance-therapy paradigm. And so we can add really great drugs in that maintenance setting, but how does that fit in our new first-line EVP world? I think that's the first thing.

But SG, if you said, how are you going to apply this specific data to your practice? Well, I'm not using much maintenance avelumab anymore, so this particular data doesn't help me much, particularly, that's even separate from me thinking about the lack of overall survival data at the interim analysis and the added toxicity of saci, when I also have saci monotherapy from a phase III study as well.

So I think, for me, there are selected patients, where I might choose sacituzumab for those patients, but I have really taken the TROPiCS-04 study to heart for most patients, and I'm not using it much in patients who have other trial options or biomarker-targeted options.

Elizabeth Plimack: Right. So a great study, a great study design, a great question in its day. Fortunately, the field is moving quickly, but maybe not practice-informing.

Jacqueline Brown: I think so. And I don't think practice-informing now, but Trop-2 is a really interesting target for us. There are lots of other drugs coming down the pike that have shown good response rates in phase I.

Whether they have issues with toxicity or efficacy in later-line trials remains to be seen. But I think there's still a lot of interest in Trop-2 as a target, because we know, with all these antibody-drug conjugates, that the target may not be the issue—perhaps it's the linker, perhaps it's the payload. And so there's lots of ways to play around with that and hopefully improve upon where we've been.

Elizabeth Plimack: And I'm sure we will in the future.

Jacqueline Brown: Yes, exactly.

Elizabeth Plimack: So you mentioned, our new frontier is frontline EVP, which has made this maintenance go away. Let's talk about EVP.

Jacqueline Brown: Absolutely.

Elizabeth Plimack: Shilpa presented some really interesting data on responders.

Jacqueline Brown: I mean, I think the take-home from that study, and I called it, in the discussion, a victory lap for enfortumab vedotin and pembrolizumab. And I think that's what it is. We are much more likely to get responses with EVP over chemotherapy. And we are more likely to get more complete responses. And the durability of those complete responses is really remarkable, with three or four patients maintaining that two years out.

So I think we're looking for an opportunity to cure some patients in UC. To be able to say that sentence to you—

Elizabeth Plimack: I know.

Jacqueline Brown: --is amazing.

Elizabeth Plimack: You said it today, and I was nodding along with you.

Jacqueline Brown: And I thought about, is that too bold? But it's not too bold because she presented data that makes that sound not insane. And so I think we have to say that. And I think it was very heartening in that way.

And now, if you're going to cure those patients, and they're going to have a continued CR at two years, well, I need them to be able to use their fingers and toes. I need them to be able to be the human beings they want to be in the world.

And so I think that's really important, thinking about, how do we start to carve out how we use pembro and EV together? Because we are unbound by any finite delivery of chemo. There's not a finite number of cycles we have to think about. Maybe we should think about that. Why are we so freed from that paradigm?

But I think carving out how we use it and how we-- I don't think de-escalate and escalate is necessarily the right word to use, it's just finding the right treatment for that patient, based on what their goals are, and how old they are, and how frail they are, and how independent they are. Those are the things we have to think about.

Elizabeth Plimack: Absolutely. So there was a high rate of neuropathy in the responders, more than in the intent-to-treat group—expected, as Shilpa said, because if you're responding, you get more treatment, and then that's what makes you stop.

But you brought toxicity, you really brought it home when you said, they can't take credit cards out of their wallet. They can't use their iPhone. They can't use their phone, which is something we take for granted, that our fingers work, that these are real impacts. I think, sometimes, when you just see the rate of neuropathy, we divorce it from that very real interaction with the world that our patients have.

Jacqueline Brown: I mean, it's like, sometimes, when I'm listening to brilliant people present, and I'm hearing about grade 5 toxicity, I'm like, that's true, but these are just like, that is obviously the n-th degree of a terrible adverse event happening to a human being; neuropathy is happening to these human beings as well. And how do we manage that?

Elizabeth Plimack: You presented a case that was relevant to this, of a patient of yours who had a CR to EVP. And we've all been fortunate enough to see those. Because the rate is 30%, it's very high, that then asked, what happens next after their second scan? With these new data, do you feel like you might have the same, different? What conversation do you have at that celebratory moment where they have a CR but maybe are starting to feel the neuropathy?

Jacqueline Brown: I know. I don't know exactly because I'm so torn by that potential that I could cure you. And if I decrease your dose or give you this prolonged break too soon, am I taking away that opportunity? But I think I'll say to my actual patient in clinic, something great has happened. This is amazing.

Our patients have been dealt bad news after bad news after bad news. You have a diagnosis. And you had muscle-invasive disease. And now, you have advanced disease. And actually, we're not going to pursue that cystectomy. You're going to go see Jackie, and she's going to talk to you about systemic therapy. It's been a rough road.

And so to get to stop and pause, and say, my friend, I have really great news for you—one, I'm going to celebrate. So I think that that abstract is a cause for celebration with patients, one.

Elizabeth Plimack: Yes.

Jacqueline Brown: And then also just thinking about, I don't know how much is enough. I had the benefit in that discussion of just posing 10 questions I don't know the answer to, and making a talk out of it.

But I think I'm going to talk to him about, I've got data that you'll do pretty well, and so let's be aggressive about managing these side effects. Every cycle, we should be thinking about it. Are we doing a dose hold?

And I tend to be pretty liberal with, hold the dose, reduce when we restart. I think the biggest thing I don't know is, in my patient case and for everyone listening, it was a patient with pretty low-volume disease, retroperitoneal lymphadenopathy, who had a CR on EV pembro. And when that's a sustained CR, and we hold the EV component, if that patient remains in CR, if he's young, and he's fit, and he wants to be super aggressive, there was a question after the session about, at the time of progression on the pembro monotherapy, would you add the EV back?

And I don't think that's an unreasonable strategy, but that is fundamentally a different patient at that point. And so I have now lost some disease control because of that prolonged break. But at the same time, no one's neuropathy is going to zero quickly. And so it's really hard to make that decision of, you've improved a little bit.

No one's life is better on EV. No one is like, give me my morning coffee and a little bitty of EV. And so I think, for that reason, it's just really hard when someone is like, I don't have active cancer, to say, your scans still look great, but we should probably go ahead and restart, because you're starting to feel good again.

So I just think that's tricky to navigate. That depends on the patient's goals. And hopefully, with the work that Fox Chase is doing, that we'll have some information on how to handle this.

Elizabeth Plimack: Yeah, hopefully, some guidance. But you're right, it's a good problem to have. It's a cause to celebrate. But then now, we want to optimize using what we have. I think you made that point beautifully—

Jacqueline Brown: Thank you.

Elizabeth Plimack: --today. Tell us about the third abstract you discussed.

Jacqueline Brown: Yeah. And CheckMate 901 is a complicated study. And we had heard about the gem/cis nivo component of this several years ago. But what was presented today was ipi/nivo compared to chemotherapy and specifically, gemcitabine and carboplatin in a cis-ineligible first-line patient population.

And the study had two primary endpoints-- one was overall survival in the cis-ineligible population. And the other coprimary was overall survival in all PD-L1-positive patients. And both ended up being negative.

The take-home for me is, this isn't a strategy for everybody. We are not using ipi/nivo next week in our clinic, because every biomarker we have queried does not have the predictive value we need it to have right now.

But to have roughly a quarter of patients who got ipi/nivo alive at five years out-- five years in oncology means, are you cured? You might be cured. And so to have a quarter of those patients-- I mean, in the renal-cell session after, we were hearing about ipi/nivo and the tail on the curve, and certainly, that's higher than what we were seeing in ipi/nivo in the cis-eligible UC population, but it's hard to ignore that for some people, it was great.

And so I think the concept is continued work from my translational colleagues on biomarkers of how we determine who's going to have this response. And how can we think about immunotherapy intensification based on those biomarkers or potentially, in all comers, in combination with a cytotoxic approach? Potentially, using an immunotherapy intensification strategy, could that allow us to limit a cytotoxic regimen along with it? Right?

Elizabeth Plimack: Right.

Jacqueline Brown: Is that a strategy to give less of the drug that's going to provide those day-to-day side effects? Recognizing that we talk about a chemo-free approach, and we say, wouldn't it be great to have a chemo-free approach? And there are downsides of immunotherapy doublets as well.

Elizabeth Plimack: Yeah, for sure.

Jacqueline Brown: Yeah.

Elizabeth Plimack: Yeah, I agree. I think you made the point that for the patients on that part of the curve, this was life—

Jacqueline Brown: Life-changing.

Elizabeth Plimack: --changing for them. And remember, cis-ineligible population, those curves all went to zero, back when we first studied gem/carbo—

Jacqueline Brown: Exactly.

Elizabeth Plimack: --when Maria DeSantis presented that. So that, to me, was like, OK, we've really made progress, whether it's subsequent lines or that line, but certainly, some of it. It's an immunotherapy-responsive disease. And—

Jacqueline Brown: Exactly.

Elizabeth Plimack: --we just need to figure it out.

Jacqueline Brown: Yup.

Elizabeth Plimack: Well, great. Jackie, thank you so much. Really, your talk was brilliant. And I think our listeners, if you have access to the 2025 annual meeting, you should stream it. It's worth it. It's a great summary. We look forward to seeing more from you.

Jacqueline Brown: Thank you for having me. Appreciate it, Betsy.