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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today on UroToday with Tom Powles, who is a medical oncologist at the Barts Cancer Institute. We're going to be discussing ESMO 2024 data, EV-302, an exploratory analysis of nectin-4 expression. Tom, thanks so much for joining us today on UroToday.

Thomas Powles: Zach, thank you for inviting me. It's a pleasure to be here.

Zachary Klaassen: I'm going to pull up some slides, and I'd love for you to present some of the data you presented at ESMO on an important exploratory analysis from EV-302.

Thomas Powles: Yeah. Zach, the first thing to say is I don't think this was the best enfortumab vedotin data presented at the meeting, so I think that honor goes to John Rosenberg and Jonathan's data in EV-103, which was the front-line cisplatin-ineligible trial. That was the prelude to 302, which was the definitive randomized phase III that has drawn a lot of attention, and which I'm presenting the biomarker data on today. It showed a five-year overall survival in this cisplatin-ineligible population of 40%. Now, I've been doing bladder cancer for a while, and I've got to tell you that I haven't seen those results before—anything like that. When we started, we were getting between 5% and 10% five-year survival, and now we're at 40%. So I think the revolution here has started. I think he also showed data on duration of therapy.

But what we have had a controversy around is the role of nectin-4 as a biomarker. And the reason why there's controversy is I think people rightly say, "Hold on a second. You've got an antibody targeting a protein. That should be important." And I think there are two parts to that discussion. The first is we've known from before that over 90% of patients express nectin-4. And then the second part of that discussion, and I think this is important, is that, at the moment, enfortumab vedotin is outperforming chemotherapy in pretty much every subgroup. And so while biomarker discovery is really, really important for the future, I don't think this exploratory analysis—or actually other analyses, which I can talk about in a second—are associated as we're trying to pick the chemotherapy population. For me, that's moved on. But in the future with HER2-targeted therapy, HER3-targeted therapy, all these new ADCs coming out, this biomarker work may turn out to be really important.

The EV-302 study is a study which you'll be familiar with. It's EV-Pembro to progression versus platinum chemotherapy—Gem-Cis or Gem-Carbo front-line metastatic disease. It hit its primary endpoint and secondary endpoints: 50% reduction in the risk of death. And here we are looking at immunohistochemistry. We're measuring immunohistochemistry out of 300 with an antibody. So if 100% of cells are positive, you score 100, and you can be 0, 1+, 2+, or 3+, and if they're all 3+ you score 300. If they're only 1+, you only score 100. So scoring 300 is actually quite difficult; it means all the cells are all expressing it.

If you move to the next slide for me, you can see on the left-hand side this yellow kind of semi bell-shaped curve. I don't know if that's the right phrase for it, to be honest. There's probably a better phrase. But this color code is—each of those bars is an individual patient, and you can see the median is 275. So that means almost all the patients, almost all of their cells are 3+. And if you look at, for example, 150, that would be, for example, half of the cells being positive at 3+. And so I think the issue with this biomarker is that almost all the cells express it, and when you consider other issues like bystander effect, it probably means that while the biomarker may be really helpful when only 20% or 30% of patients' cancers progress, it may be less helpful here. It's notable only 10% of patients have expression of less than 150. So it's a relatively small group scoring less than 150.

If we move on to the next slide, you can see actually there's no major difference between expression in either the primary tumor or the metastatic sites—they're both high. And if you keep going for me, the quite good place to start is the median at 275. And you can see when you're above and below the median, it really makes very little difference from a PFS perspective. The hazard ratios are in the 0.4s, and the same—0.4s and 0.5s—from an overall survival perspective.

And that comes to about what I said previously, which is that I think chemotherapy is being outperformed consistently. But disitamab vedotin, HER2-targeted therapy, 75% response rates in HER2 1+, 2+, or 3+. It's possible if you end up with 95% response rates in 3+, you might want to look at this again and say, "Well, what about this patient with a low nectin-4, HER2-high?" That's where I think this data, I hope, will become relevant in the future.

The response rates, as you would expect—you can see the outperformance of EV-Pembro compared to chemotherapy. I'm going to draw your attention to the right-hand side of this curve. This is going down to the lower levels—the H-score less than 150, between 150 and 225, and above 225. And these are the much lower levels. So that left-hand, that less than 150—that's 10%, that's the lowest 10%. We've looked at that population in detail. Now, the confidence intervals are wider because it's only 10% of the population. But essentially you can see with this low group, EV-Pembro is still outperforming chemotherapy.

We can slice it and dice it different ways, and we're now getting very exploratory. The top left-hand curve—you can see here they're low for PD-L1 and low for nectin-4, because remember, we are with pembrolizumab, which is a PD-1 inhibitor. The biomarker doesn't work; the PD-L1 biomarker doesn't work particularly well in this setting, so it shouldn't come as a big surprise that the PD-L1 is not discriminatory. But actually they're quite well-balanced. Patients are quite well-balanced between PD-L1 high and low, and nectin-4 high and low. All four groups, as you can see from the numbers at risk, are quite well represented here. And in all four groups, again, slightly unexciting story for EV-Pembro consistently outperforming chemotherapy. Some of the tails of the curves, the numbers get down to 2s and 3s, and I wouldn't overinterpret the tails of subsets of curves in too much detail.

And so I think it's fair to say that the discussion around the biomarkers for EV-Pembro is ongoing. This is the first prospective randomized trial to explore that. There's been retrospective data on amplification and immunohistochemistry and other approaches which have suggested there may be a trend towards benefit on higher levels. We've not seen that in EV-302. Actually, what we've seen is consistent benefit. And I think it does, though, lend itself to that piece. I've said this before. I remember when sunitinib transformed renal cancer and it beat interferon; at that point it was so much better, and we didn't make that effort to look for biomarkers because it was better, and we never developed biomarkers for sunitinib and pazopanib. That ship sailed. And now when immunotherapy came along, we regretted that. And only now are we beginning to identify good markers for sunitinib 15 years down the line.

So I think it's fabulous that this work is ongoing. It should continue, and I hope that we will have even better drugs in the future. And I hope we do have a personalized approach where EV-Pembro plays a role in that 10, 15, 20 years down the line.

Zachary Klaassen: Absolutely. Great presentation, Tom. I'm going to quickly go over my first question that I kind of wanted to ask you because I think I know what your answer is. There really was no surprise, because of the high expression of nectin-4, that all of these patients beat chemotherapy, correct?

Thomas Powles: I think there was no surprise that there was no subgroup where chemotherapy outperformed EV-Pembro. And that's partly, as you said, because almost everyone expresses some nectin-4 and these drugs seem to have a bystander effect. I think some of the work with the amplification, which is a smaller group of patients, is interesting. And there is a question that we should try, and that's something that group, I think in Germany, should continue to pursue.

As it stands at the moment, I don't think we're ever going to find a chemotherapy group that you said, "Okay, we've got this amazing regime with 30% CR rates, three-year overall survival or whatever it's going to turn out to be in the future, median overall survival. We should be giving them chemotherapy instead." I just don't see that happening. But I do hope that the conversation will evolve with the second generation of ADCs that are coming through.

Zachary Klaassen: Yeah, and that's the next question I want to jump to. We're just over a year from EV-302, and we've all had the patients where they're disasters; also, they're one of the 30% that has a CR. Everybody's excited. Let's take those patients that maybe either don't do as well or even progress on EV-Pembro. And I think this is going to lead to your other point. Are we looking for maybe HER2, HER3, other ADCs? Is that the next sort of mountain we have to climb to get the patients that maybe aren't responding to EV plus Pembro?

Thomas Powles: I think there are two parts to this as well. The first is, I think you get one really good go at urothelial cancer. And so while I think sequencing ADCs—as is ongoing in other tumor types, breast cancer, lung cancer, et cetera—I think that's something which is important to explore, and I think we can do that successfully. But a more important question is, can we move these into the perioperative space and cure more patients?

So my first priority is to say, let's cure more patients in the perioperative space, because in the end, EV-Pembro failure is going to be more of a palliative setting. But then the second part, which is actually, I think, really exciting is we saw at ESMO—again, I saw some really impressive data on disitamab vedotin, which is a HER2 ADC. We saw data for a HER3 ADC out of China. We saw updated data on the disitamab vedotin in combination with immune therapy with pembrolizumab with 75% response rates. We saw data on new nectin-4-targeted therapies with 40% response rates. We know there's data on TROP-2 ADCs with sacituzumab govitecan and second-generation TROP-2 ADCs. We've also seen data for sacituzumab govitecan in combination with enfortumab vedotin.

I was speaking to a French colleague yesterday. He was a surfer, and the bladder community has been sitting out in the sea waiting, on our boards, watching the state doctors catching beautiful waves somewhere else at a different beach, boating us up. We've been sitting in the water waiting for these waves to arrive, and a beautiful set of waves has arrived, and there is an opportunity to transform—dare I say cure—these diseases. And I think that goes beyond just EV-Pembro. I think the second generation of drugs has an important role to play.

Zachary Klaassen: Beautifully said, Tom. Thank you so much for sharing insights on EV-302 and the nectin exploratory analysis and for your time, as always, on UroToday.

Thomas Powles: I enjoyed talking to you, Zach.

Zachary Klaassen: Thanks.