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Ashish Kamat: A warm welcome to all of you from the UroToday studios. I'm Ashish Kumar, Professor of Urologic Oncology at MD Anderson Cancer Center in Houston. We're live here in San Francisco at ASCO GU 25. And it's a pleasure to welcome Tom Powles to the venue. Thank you, Tom, for being here.

Thomas Powles: Thank you for inviting me.

Ashish Kamat: It's always exciting to sit and chat with you. And of course, with the EV paradigm, you're going to be talking about the updated data from EV 302 at the meeting here. So share with us some of the background for some of the audience that might not be familiar, and then what's new.

Thomas Powles: I'll be as brief as I can. So platinum-based chemotherapy, the standard front line for advanced urothelial cancer for 40 years. Platinum GemCis, GemCarbo, not great outcomes, honestly. Median survival between 12 and 15 months. Response PFS about six to eight months. Pretty toxic six cycle, speaking frankly. Immune therapy came in, but largely second line, and then maintenance therapy. Actually, the median values didn't shift the goalposts that much in the grand scale of things.

It looked like chemotherapy and immune therapy was somewhat antagonistic against each other. Single-agent immune therapy wasn't as good as chemotherapy at getting control. We thought we'd reached a plateau. Then the antibody drug conjugates came along.

EV is a single agent, 40% response rate in heavily pretreated patients. Twice as good as anything we've seen before. And then when you combine it with pembrolizumab in the phase II studies that Jonathan Rosenberg and other people led, we saw 70% response rates rather than 40%.

And so this related in a big change in the way we thought, so we launched a big randomized phase III study that was presented at ESMO last year.

In that study, we showed reduction in the risk of death by 53%. Reduction in the risk of progression by 45%. Hazard ratios in the 0.4s. Sorry, reduction in risk of death, 55%. Hazard ratio of 0.4s. Not seen that before.

But we didn't have durability at that point. We had about 13 months of follow-up. And so the curves are a bit unstable. What we presented here is 26 months of follow-up. And we now see that these results are sustained, which is fabulous.

Still, the hazard ratio is both now around 0.5, so 50% reduction in the risk of progression, 50% reduction in the risk of death. 30% CR rate—3.0. Like, going back in time, 30% CR in bladder cancer, amazing. And if you look at that CR population, 75% of those patients are progression-free at two years. 75% progression at two years. Over 90% are alive at two years. That's 30%.

And then if you look at the overall population at the two-year landmark, 60% are alive. The median survival is clearly three years. These numbers were numbers that if I went back in time and said we were able to achieve that, I would have been amazed.

And the other piece, the durability of response, we also saw just the responders—not just the CRs—doing exceptionally well. So we saw in that population, 50%. So 70% of patients are responding, about 68%, and of those 70% of patients at two years, 50% of them are still responding.

So this is just a change in the way we treat the disease. One of the key questions from here for me: how long do we keep going?

Ashish Kamat: Right, exactly.

Thomas Powles: And that's one of the real questions.

Ashish Kamat: So what's the answer there? How long do we keep going? And what's your sense as to how much of this a patient is willing to tolerate and can tolerate?

Thomas Powles: Look, it's becoming really difficult, because when you meet patients and say you've got this lethal disease—and you've got—I see patients with bone metastases who have come in, they've been told that it's a lethal disease and things go wrong quickly with chemotherapy. You put them into a complete response. Many of those patients don't want to stop.

Now, skin toxicity is an early problem. And I don't think it's a huge issue, providing you're prudent and stop and interrupt, reduce and then rechallenge a low dose. So that's really important. But peripheral neuropathy does build with time.

And so you need to be giving treatment holidays, time off therapy. Is a year too short? I think it probably is. Is five years too long? Obviously, it is. Is everyone going to be the same? Absolutely not.

I look at it a bit like a tornado passing through a regatta of ships—every ship going in a slightly different direction. The toxicity requires attention long-term. This is not abiraterone. It's more toxic than abiraterone. I don't think it's more toxic than six cycles of chemotherapy. I think six cycles of chemotherapy is more challenging than six cycles of pembro.

But years and years of EV pembro can be associated with adverse events. And so we need to work out actually how long is right for each patient. I don't think doing discontinuation trials is going to work, because the patients who I see, many of them have made their minds up on what they want to do.

Many patients are desperate. I've got grandchildren, I've got this, I want to see my son, I'm not stopping these drugs for being a CR. So lots of people saying that. Other people with peripheral neuropathy saying, I need some quality of life back. I need to be able to walk more. I want some time off therapy.

So I think it's just a really exciting time in bladder cancer. I think EV pembro is changing things.

Ashish Kamat: No, absolutely. And again, congratulations on everything and all the work that you've done.

Thomas Powles: It's a big team.

Ashish Kamat: I still remember us chatting and talking about when we went into bladder cancer, we were told, all your patients are going to die. And that was true for a long time. And now, of course, we have something we can offer our patients.

But even with these excellent results, we still have patients that do not respond.

Thomas Powles: Yeah.

Ashish Kamat: What's your sense from all the work you've done? Are you able to identify, leaving aside CRs and actually what happens, who is not a good candidate for this combo?

Thomas Powles: Yeah, so two things. Number one is, does the biomarker work well? It looks like over 90% of patients express nectin-4. It really is quite heavily expressed in bladder cancer. I don't think that's going to solve our problem.

Now, it's possible that there are patients with amplifications or DNA changes to nectin-4 potentially that have extreme responses. And it's conceivable in the future that we could find other biomarkers, such as HER2 expression, HER3 expression, where they may work better in patients with higher HER2 and low nectin-4. It's conceivable. We have to answer those questions.

One of the things I remember from the renal cancer experience was sunitinib was a transformative drug, as well. And at that point, we didn't do any biomarker work, because we said no patients were going to give interferon rather than sunitinib. So let's just forget it.

But actually, we look back on that as a mistake, because when immune therapy came along, we didn't know who the VEGF-targeted therapy worked for. So let's not make that mistake again. Let's do the biomarker work—not define the chemotherapy patients, but define the next generation of drugs to do even better.

Ashish Kamat: And speaking of HER2, I mean, again, right now we don't select patients for EV based on HER2. But there is data coming out of China, which will be presented here at this meeting, as well, which you're well aware of—are you of the thought process that we can then use HER2 expression, for example, to select for alternative ADCs? Or you would still recommend EV pembro based on everything we know so far?

Thomas Powles: Well, there are two randomized trials for reading out—well, one reading out from China with DV toripalimab versus chemotherapy relatively soon. Will it reproduce EV 302? Possibly, I don't know.

Will we do DV toripalimab versus EV pembro? I don't think we'll do that trial. I suspect it would show there might be about the same. We'll have to wait and see. It's going to be very hard to get hazard ratios of 0.4s in the future, I think.

So then the question is, can we find the biomarkers to do that? And I think we may be able to do that. HER3 plus, we know T-DXd is approved in that group, and it might be that enrichment in the heavily expressed HER expressors.

There was some data on DV pembrolizumab that Matt Gowski presented at ASCO this year with high response rates, 75%. So it's possible that we can achieve goals of doing even better.

But then the question is, do we build on top of EV pembro with triplets? And if we were to do that, how would that be? And then the last question is, what's the mechanism of resistance? I think the payload is generating the resistance.

So I think EV and DV will have cross-resistance. So DV pembro follow, EV pembro first, followed by DV toripalimab, I don't think is going to be the right answer to this question.

I think the data which I'm excited about at this meeting is there is some new Trop2 Topo1 ADC data, and there are two trials, both with response rates that look promising. You might remember that sacituzumab govitecan, which is also a Trop2 SN-38 ADC, failed to beat single-agent chemotherapy. There was a toxicity signal within that. And I think these second-generation drugs, which have different linker molecules, potentially different toxicity profiles, but also, we learned from the first generation. So we might be able to take these drugs forward. And of course, there's also the HER3 ADC, which I'm very excited about.

So I look at this field and think, can we beat pembro? Quite hard at the moment. Can we find some patients who do better? Possibly. Have we got other new exciting agents? Absolutely. New combinations, new sequences.

And of course, EV pembro in the very near future is going to end up, in my experience, in the perioperative space, neoadjuvant curing patients. And you and I have chatted about this before. I think that we're going to stop doing cystectomy in big groups of patients, because we're going to cure patients with systemic therapy.

Ashish Kamat: I sure hope so. I would love to put myself out of business with the CRs that you see or the Pat CRs that we see, and if you can translate that to clinical complete response and all of that.

That's not the topic of this, but since you bring that up, what's your sense with the 60%, 70%, 80% CRs that we're seeing, Pat CRs, how durable do you think that will be once you stop treatment with EV pembro? Because as you just said, you can't take them on forever. And these tumors will recur in the bladder at some point.

Thomas Powles: Yeah. I think this is an area that we need to define. I think we have to ask the questions. This is an area which I'd like to explore. There's some data on chemotherapy and nivolumab, where it looks like the cancer does come back locally in some, but not all patients.

I think I wouldn't dare say we're going to put you folks out of business. We may end up giving you more, actually, because those patients will require local management with cystoscopy.

But one thing I know for sure is that with these really active drugs and the desire from patients not to have a huge operation in the eighth decade of their life, I think that this is going to turn out to be one of those things that happens quite quickly.

I think the local relapse rate is going to be modest. And I ask you a question about whether you think it's the same cancer, or do patients with unstable bladders—actually, is it just an increased chance of generating an unrelated cancer also, because the bladder is still there?

Ashish Kamat: Exactly. And I think that's where the paradigm will shift. We'll cure the invasive cancer, and then we'll have to treat them with intravesical therapy, whether it's the TAR device or BCG or whatever, to actually treat them like their chronic bladder cancer patients.

Thomas Powles: And we're going to use ctDNA.

Ashish Kamat: Absolutely.

Thomas Powles: We're going to bring it all together. It's going to be really good. It's going to be amazing. We've got some fabulous singles. We're going to make an album.

Ashish Kamat: There you go.

Thomas Powles: Like the Stone Roses.

Ashish Kamat: Exactly, there you go. Tom, always a pleasure to have you.

Thomas Powles: It's been lovely. Thank you.