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Zachary Klaassen: Hi, my name is Zachary Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Neal Shore, who is a urologist at the Carolina Urology Research Center in Myrtle Beach, South Carolina. Neal, thank you for joining us on UroToday, as always.

Neal Shore: Great pleasure. Thank you, Zach.

Zachary Klaassen: Today, we're going to have a case-based discussion, so a little bit of back and forth, and really highlighting the first-line treatment for metastatic urothelial carcinoma, the EV-302 data, looking at enfortumab vedotin plus pembrolizumab. I know you and I both have patients in our practices that have benefited substantially from this over the last about year or so since FDA approval in December of 2023.

So what I'm going to do is just highlight a case of mine that I think will set the stage for our listeners in terms of where they can see this working in their practice. You and I are both surgeons. If we take out a bladder, we're obviously expecting this not to be metastatic, but some people will become metastatic. So we're going to talk about that today. Certainly, first-line metastatic human patients present with metastatic disease is also an excellent indication.

So without further ado, this is a 72-year-old veteran who presented with gross hematuria for about six months in August of 2022. He had a TURBT in September of that year showing urothelial carcinoma, a 6-centimeter tumor. He had staging negative, so he was a clinical T2N0M0. He was referred to my clinic for consideration of neoadjuvant chemotherapy and radical cystectomy.

This gentleman had a history of head and neck squamous cell carcinoma. He was NED for about five years when he saw me. He had hypertension, hyperlipidemia. He had a-fib with a pacemaker, but otherwise very active, ECOG performance status of 1. He played golf three times a week, married. He did have a 50 pack-year smoking history as well.

The key labs at the time of his muscle invasive bladder cancer diagnosis was eGFR of 52. So we saw him in the clinic. He underwent four cycles of gem-cis neoadjuvant chemotherapy, did reasonably well with that. We went and did the radical cystectomy bilateral pelvic lymph node dissection in March of 2023. Pathology was ypT1N0 R0M0 urothelial carcinoma with some sarcomatoid differentiation.

So at that point in time, he was on a three-month surveillance imaging regimen, which was negative until April 2024. He had an FDG PET ordered by our medical oncology team which, unfortunately, showed several lesions, one in the lung and one in the left pelvis, which you can see here highlighted on the FDG PET.

So at this point in time, we presented him at our tumor board, and the consensus was for biopsy of the right lung lesion. This unfortunately showed metastatic urothelial carcinoma. His eGFR post-cystectomy, which is not super uncommon, did take a bit of a hit. His eGFR was 39 at that point.

So Neal, this gentleman—still good performance status, a bit on the shaky side from a kidney function standpoint, not disastrous metastatic disease, but what sort of treatment options are you going to speak with him about?

Neal Shore: Well, it's a good case. It's very classic in so many ways. Although I have to say, I mean, I'm a little bit—he's a performance status of 1, and he golfs three times a week. I'm like, all right, based upon that, I'm probably a performance status of 10. But just—

Zachary Klaassen: He's a vet, though. So he's tough, Neal. He's a vet. He's tough.

Neal Shore: Yeah, I love that he's playing golf three times a week. Yeah, no, he's got some comorbidities and yeah, that's a good question. I think that right now, for me, I think it's great that you were able to do the metastasis-directed biopsy. I always aim for that. I work very closely with my interventional radiologist. It's good because you want to rule out that this is not something else. And that's really important.

I think, for someone like him, this is concerning. He's got a pelvic lesion, he's got a visceral lung lesion, and he's got, clearly, metastatic disease. Clearly, he did well with his cystectomy. He had some sarcomatoid variants. I think, at this point, some might consider radiation therapy. Maybe I'd be a little bit more inclined if it was an isolated lymph node lesion. I typically don't go to that. I would consider that he's clearly metastatic and I'd be thinking about systemic therapy.

He had his neoadjuvant chemotherapy, which I think is great. The data clearly supports that. Spot on. I think my read of the market today is 75% of patients are getting NAC, which I think is great. Now we've recently had some new data presented in the NIAGARA regimen at ESMO, maybe that's going to change now with perioperative addition of durvalumab.

But he's now metastatic, so that's the question—what are you going to do next? And I think, right now, front-line therapy, the new standard of care for the right patient, which is the overwhelming majority, would be the combination of pembro and enfortumab vedotin.

Zachary Klaassen: Yeah, absolutely. I think, again, we presented him follow up at Tumor Board. And again, timeline was December 2023, approval for EV plus pembro. This is April of 2024, so we were fortunate at that point. Also fortunate because his eGFR was getting a little bit on the soft side in terms of being able to give him additional chemo. So that's exactly what we did. I'd love for you to walk through some key slides here from the EV-302 trial, which was published with Tom Powles and colleagues in the New England Journal in 2024.

Neal Shore: Yeah, thanks, Zach. Super happy to go through this pretty quickly, I mean, because I want the readers to—you should read this paper. I had the good fortune of being in Barcelona when—was it Barcelona or Madrid? I forget now. But it was in Spain. And Tom gave this presentation, and there was a standing ovation. I had never seen anything like it because the data is so amazing, and Tom is a great presenter.

We didn't participate in the study. I actually participated in the cohort K of the EV trial, which is in second line. And I started using enfortumab vedotin, which is commercially now called PADCEV. And this is an antibody drug conjugate, its payload is MMAE, —it works on NECTIN-4 expression, which is north of 90% of patients. You don't even need to check for it.

But the bottom line here—this was a great global study. These are previously untreated patients with locally advanced or metastatic urothelial carcinoma. They had to be eligible for platinum, EV, and pembrolizumab, as you can see here in the schema. No prior exposure to a checkpoint inhibitor.

It didn't matter if they were IHC positive or not. And they just needed to have a GFR of greater than 30. And there was a one-to-one randomization of EV-pembro versus additional chemotherapy. And the chemotherapy—they could get cisplatin or carboplatin. At the end of the day, it didn't matter. EV-pembro beats both, especially the platinum versus the carboplatin arm.

And the dual primary endpoints—progression free survival, BICR, Blinded Independent Central Review, very important, and OS. And of course, it knocked it out of the park in both. And I think we're going to show those, I hope. And the usual secondary—and then this is what was so, quite frankly, phenomenal. I wasn't shocked, but I was surprised because I had worked with EV before. But this was kind of—at 12 months, I mean, look at the difference in the PFS. I mean, it's more than a doubling in terms of the beneficial effect—hazard ratio of 0.45. I mean, it was rather astounding. And that's where the people were just going crazy.

And you look at the subgroup analysis, regardless of age, race, location in the world, male, female, ECOG 0, 1, presence of upper tract/lower track, liver positive or not, regardless of the PD-L1 expression, whether they got a platinum or carbo—everything favoring the treatment arm of EV-pembro. This was in comparison to frontline chemotherapy.

The OS—bam. I mean, a hazard ratio of 0.47. I mean, yikes, a 53% improvement in overall survival. You're looking at the various 12 month, 18 month, and continued analyses. I mean, you might not be able to drive a truck through this, but it's an awfully big car you're going to get through here. And so this was super exciting. And this is a big deal. And congratulations to all the investigators all over the world. And again, subgroup analysis—wow, everything favoring the combination left of the one hash mark. So this was tremendous. This was a real advance in the field.

Zachary Klaassen: Absolutely.

Neal Shore: And then you get over here—the overall response and the duration of the response—a complete response, 29% versus 12% in adjuvant chemo, really balanced. The demographics on this were totally balanced. Partial response also favoring, and so everything down the line to confirm—median time. This was really great, and that's why it's now been put into everyone's guidelines. This is pretty much global incorporation of guidelines since it came out—super fast that it occurred.

Zachary Klaassen: Yep, no question. So you're absolutely right. My patient was fortunate enough to be in that 29%. He started EV-pembro in June of 2024. He's still getting his imaging every three months. At six months, he was NED, complete response. And so I think the one thing I want to touch on—he had the classic EV-pembro side effect. So he had some lower extremity peripheral central neuropathy, had some inner groin upper extremity pruritus. But he continues on—he's doing fantastic. His quality of life is excellent. He's still playing golf. So maybe, Neal, just take us through some of these treatment-related adverse events.

Neal Shore: Yeah, so both pembro—all the IOs and the checkpoint inhibitors—you can see rash. And you can see rash with EV. You tend to see the rash with EV a little bit earlier, but rash is real. And so one needs to be cognizant of that and associated pruritus. And you see the maculopapular rash down there. It's in your fourth note there. You don't really see much in the way of alopecia of really grade 3s. But you can see this rash, which clearly was more significant than what you saw with chemotherapy. I think, with the chemotherapy, you tended to see clearly more neutropenia. And you see that at the very bottom here.

But the real call-out is the neuropathy. You can see neuropathy, of course, with platinum-based therapies. But the neuropathy, the grade 3s especially, was higher. And you see a lot more of it even in the low grade. One of the nice things is, which is good, is—look, neuropathy is a tough adverse reaction, especially if you want to do things that you're dexterous and even if you're not.

I mean, losing touch, inability to walk comfortably, and having numbness in your feet—I think this is really important because it's raising the bar in the field about understanding initial evaluation for possibilities for developing neuropathy. So getting a good baseline neurological exam regarding ability to use buttons, tie shoelaces—if you're particularly someone whose dexterity is really important to you, maybe you're a piano player or a violin player or something like that.

But you do see neuropathy with this particular antibody drug conjugate geared towards NECTIN-4 with an MMAE payload. The MMAE is really the reason. The nice thing about it is if you recognize it—and it's important to be aware of it—you can dose reduce, you can dose interrupt, and then you can restart at a lower-dose modification. The drug is not continuous. There is a sequence for it in terms of three weeks on, a week off. But then again, you can dose reduce. You can even change that schedule a little bit.

Now that's not necessarily all in the label, but I think once you start getting a little bit more comfortable with this, these are options for the patient and the physician team to think about.

It's worth bringing this on because it really is a remarkably clinically efficacious combination.

Zachary Klaassen: Yeah, no, absolutely. I'd love for you, Neal, to maybe just highlight for our listeners, over the last year in your practice, how you've seen this sort of change and what the patient experience is. We talked about AEs, but how are they reacting when they get this complete response? We haven't seen this kind of data in locally or metastatic advanced urothelial carcinoma to date.

Neal Shore: Yeah, it's a great question. It's funny, and patients—they're n of 1. So they don't really—at least in my patients, they're not doing a literature search, and they're not following everything. And so when I see these complete responses and these marked improvements, I'm high-fiving, I guess, myself. I'm high-fiving them and their families. But they're like, oh, no, this is great. You told me I was going to do well.

This is a very bad biology when patients develop metastatic urothelial cancer. This is much worse than the typical average patient getting metastatic prostate cancer, just kind of keeping it in the realm of GU. And so when you see these levels of response, it's just exceptionally gratifying.

I do think this is another really great example of the importance of the multidisciplinary team. So the uro-oncology team—like you did. I mean, you did it kind of perfectly. You did the cystectomy, you knew to get them to your medical oncologist to give the neoadjuvant chemotherapy. He did initially well. Then he recurred. And then you got him into the right group. And this is optimizing patient care.

And I think, really, this is a remarkable regimen now, the EV-302. And I think that this is a real advance in the field.

Zachary Klaassen: No question. I think, just to round it out, we are going to probably see this move up in the disease space as well. I know we have trials going on in the neoadjuvant space. I think if that trial is positive, that's going to be incredible for our patients, particularly in those patients where their eGFR is getting in that 25 to 35 range and it's really difficult to give them something else, such as cisplatin-based chemotherapy. So I think that's going to be coming down the pipeline. We hope that trial is positive.

Any last minute comments or take home messages for our listeners, Neal?

Neal Shore: No, I think you nailed it with that. When we basically see the development of EV, we had it in second line. Now we see it in front line. Now it's getting clearly trialed in neoadjuvant strategies, bladder-sparing strategies. And there's even work in it in nonmuscle invasive bladder. So I love it because this is how we advance the field.

Zachary Klaassen: Absolutely. Neal, great discussion, as always. Thanks for your insight and for your time today on UroToday.

Neal Shore: Thanks, Zach.