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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 joined on UroToday with Dr. Josh Meeks, who is a urologic oncologist at Northwestern University. Josh, thanks again for joining us on UroToday.

Joshua Meeks: Thanks for having me, Zach.

Zachary Klaassen: So we're going to talk about a presentation that you had at SCO 2024, really looking at—are we at the time where we should be thinking about moving away from single-arm trials in the BCG-unresponsive space? And I know you've got a couple of slides to help launch our discussion. So why don't you pull those up and present that?

Joshua Meeks: Yeah, sure. And so here are my slides, and I just try to go over the top highlights of what we talked about in Dallas. And so, the overall theme of this was that we really are at a completely unique place for BCG-unresponsive bladder cancer. For decades, we've said we just don't have enough drugs, and we don't know what to do with these patients. And ultimately, for many people that are faced with this situation, as you know, it's like, are you going to have a cystectomy now, or are you going to try something and then a cystectomy? Or worse, do you have a risk of progression? And that's really the worst case of this.

But really, for now, we're in a completely different place because if a patient walks in, they have three FDA-approved options: Keytruda, Anktiva, Adstiladrin. They have a very good non-FDA-approved option: gemcitabine/docetaxel. And really, when the practitioner is sitting there trying to figure it out, they really don't know what to do. And I think really the concern I'd have is you take those four options, and now you'll have two more coming.

And as we've talked to our patients, we can talk about, well, this is what individual single-arm trials show, but really, there's never been a comparison. And that's because all of these drugs were approved through single-arm Phase II trials. That was really set up as a mechanism to get drugs into this space. And so I would say we could declare a victory there. We actually have drugs at this point that we can give patients. But you and I are left trying to figure out how we have these talks with our patients and try to compare among trials and say, “Well, this one could be a little bit better. This one may have a little bit less toxicity.” And for drugs that we've not worked with in the clinical trial setting, many of us are just trying to get some experience with them. So I think it's getting to the point where we need to put away the single-arm trials and start comparing across trials and really doing randomized controlled trials.

Zachary Klaassen: Right.

Joshua Meeks: So that's kind of the point of what this talk was—to say, going forward to 2025 as 2024 wraps up, how would we do this? And I think the big issue that many people have is like, OK, I have my special drug; how do I compare that? What would be a good comparison? And I'd say, well, first of all, again, right now you have a bunch of options. You've got four options you can use as standard of care. And it doesn't necessarily have to be that every single trial uses one standard of care. We know, for example, that many of these drugs act in a very similar way, or if you compare them, they're pretty close within a standard deviation of each other. So it doesn't have to be that there's one drug; you can compare many of them. And in many cases, those drugs have very similar efficacy. Additionally, you don't talk about too bad a cost because you could randomize 2:1, where a patient gets two times the experimental drug versus a standard arm. So there are certainly ways to do that.

I think a very standard randomized controlled trial would be drug A—which would be the experimental drug—versus drug B. And most of these trials have a primary endpoint of a complete response at any time. But as you know, for patients, if they have a complete response at three months but then by six months they're having a cystectomy, that's not a durable outcome. So I really think our 12 months should be the landmark for durability. And maybe you say a secondary endpoint is a complete response, because we have something to compare to. But really, it should be what percentage of patients who start on day one make it to a year with a complete response.

And as far as outcomes go, I really don't think that we're trustworthy as investigators. I really think patients should have tissue-based evaluations. And again, to me, I would just propose three months and 12 months to be those time points where a patient on this trial would get blue-light cystoscopy and mapping, really to be able to compare apples to apples. So this is, again, very simple: drug A, which would be the experimental arm, versus a standard of care is drug B.

One option that we talked about—because, again, rather than having to reproduce this with every single drug—would be to use an NCTN mechanism. And the NCI actually had a workshop about a year ago, where they said this is actually a very feasible plan. And the analogy would be for prostate cancer: STAMPEDE. So in STAMPEDE, as you know, there's a lot of good drugs. We don't always know the best space and the best patient population to use them. So there's an experimental arm and a standard of care, and then as new drugs come up, they get nominated, and they get added to the list.

And so there's some potential benefits for the companies and for pharma here. Number one is if you think about—if this goes to the NCI cooperative network, there's a lot of trial costs that get deferred. Right now, the bar is relatively low, but if we raise the bar—if we raise our expectations that a trial or a drug has to compete in this space—then that almost pushes it to that point. So I think this would be great for patients because you can just keep adding different agents onto this trial and have a relatively simple mechanism where a drug that has some activity, once it meets a certain bar, it can go into this comparison mechanism and really compete as a standard of care.

Zachary Klaassen: Yeah. Josh, I think this is a great slide. And you look at the prostate cancer—you mentioned STAMPEDE. There's no STAMPEDE 2. And there's going to be some excellent stuff coming out of that with lutetium, etc. But we're almost set up perfectly in the bladder cancer space.

Joshua Meeks: Yeah.

Zachary Klaassen: We have multiple approved agents now. We have some exciting stuff—TAR-200—coming down the line at some point. So would you say—and you highlighted it a little bit—would a cooperative group run this? How would we do it? Because obviously NHS runs it in the U.K. How would we really rationalize this, and how would we operationalize it? Because it's a great idea.

Joshua Meeks: Well, again, I think—so I put Scott Delacroix's picture there because he was the brains behind this at the workshop. And again, I think you need NCI, you need the Bladder Cancer Task Force (which all the cooperative groups are a part of), and again, you need a lot of patient representation on this. But I think it would have to almost be a federal mechanism because, again, in a lot of ways, that keeps the field plain, where everyone comes in at a certain level. You set up criteria. And again, the benefit for pharma is that a lot of that infrastructure is covered. I mean, obviously, they would provide drug, but you would hope that the mechanism to really evaluate these therapies and say who's the best in this setting could be managed this way. And again, as you point out, for many of our patients, it's rare that they get one shot on goal. They often have multiple therapies that they'll try. And so having patients in, and they can potentially move from one arm to the next as new therapies get nominated, that's also a very reasonable option for patients.

Zachary Klaassen: Yeah. Absolutely. And I'll actually ask one more question about the previous slide when you talk about sort of that head-to-head. How would we get—because obviously, drug A may be one company, drug B may be another company, maybe it's BCG rechallenge—any insight into how we can get industry, cooperative groups, maybe the NCI, maybe even the VA? How do we get them all to the table to design these RCTs?

Joshua Meeks: Yeah. I think that's one of the challenges with doing the A versus B kind of comparison, is how you actually set that. And again, Zach, could it be that the standard of care in Augusta is different than the standard of care in Chicago? But if we're all hitting the bar of 30% to 40% at a year, and the trial is well enough built, then that noise should go away if drug A is that much better. If it's no different, then I'm not sure drug A really should be in the field. But I think we're starting to see that. And I think the best example of that—because this is actually already starting—so SunRISe-5 is a Janssen trial. Again, that trial is TAR-200 versus standard-of-care chemotherapy, which can either be gem or mitomycin. And again, both drugs are not FDA approved necessarily, but you have a standard there that is investigator dependent. And again, what you may want to give a patient, I may want to give the patient, as long as it's within a modern range. I think that's kind of how I see being a permissive way to begin that.

Zachary Klaassen: Yeah. Great point.

Joshua Meeks: I think the last thing, trials on—I kind of want to point out, and again, I give Mark Tyson a lot of credit here—is this crossover design. Because again, a lot of patients don't usually just do one therapy and then choose to get off trial. Many of them, when they sign up, their goal is cure and bladder preservation. So this trial concept, which is coming through SWOG, can say, well, how well does drug do in first line? And then following drug B, how well does it do? Because, as you know, each therapy really changes the microenvironment of the bladder. If you look at a BCG bladder versus a chemotherapy bladder, they look totally different. The chemotherapy bladder is usually very sterile. You don't see any immune cells. The BCG bladder is full of neutrophils, and it's almost like a snow globe.

Zachary Klaassen: Yeah.

Joshua Meeks: So you've got to imagine that if you have an immune modulator, it's going to be different coming after BCG than, like, chemo. So that crossover data is really important. And again, I think that there's a lot of advantages to considering these crossovers, where patients sign on for one, and if a recurrence occurs—as long as they're not progressing and they meet certain criteria—they get to move on to a second option.

I realize that this randomized controlled trial is probably not going to happen right away. But I think while we're still in this gray zone of single-arm trials, there's some things that we can do to make things a little better, because right now, again, I think there's a lot of heterogeneity in the patients and how the trials are set up. So again, I would advocate for central pathologic review of the specimens. I actually think central review of the cystoscopies is important. If you have a single-arm trial and it's only viewed by a single person, that red spot may mean something different to you versus me, and some patients may get a biopsy and others not. I kind of think a blinded person should be involved in that. And again, recording that with an iPad, for example, is very practical. Again, I'm for mandated biopsies. I think if that's negative, you and the patient feel a lot better. And again, I'd advocate for some durability as far as 12 months being the primary outcome.

So this was essentially the summary of the talk, that we really need to be moving to randomized trials. The risk with single-arm trials is that if approved, they kind of lack utility in a lot of cases. And there's a lot of ways to go about that. And really, we should be working together with pharma and the NIH together to try and fund and develop these trials and biomarkers in these settings.

Zachary Klaassen: Yeah. Wonderful talk, Josh. And I think the one question I want to follow up with is—as we move into 2025, let's say we get some of these trials designed and we fast-forward a year or two, and we have some head-to-head comparisons. Obviously, we want a biomarker that says, we have five options, let's start with this, and if that fails, we'll go to this. But is there a way that potentially by starting to get some of this head-to-head data, we could start to sequence a little bit more efficiently and provide patients with not only what we’re going to do next but maybe it's time for cystectomy? Is there a possibility that we start to learn something about the sequence of drugs?

Joshua Meeks: Yeah. I mean, I definitely think, for example, you intuitively have that already in the sense that if you look at a bladder that is bright red with CIS, and you give BCG and there's no budging of that, and you have CIS where the whole bladder remains blue-light positive, I think it's a very different bladder than one that has a tiny little area that you only find with blue light. So there's already some clinical information from that. Now, the main question that we're going to have is, can you quantify that? And there are some urine tumor assays that can get that and actually give a better readout. So for example, if you're not able to give a patient blue light, or someone's not able to do the endoscopic procedures that all of us do necessarily, you can have a number, for example. So I think those kinds of assays are coming along and will help, again, decrease the heterogeneity of these patients across trials.

Zachary Klaassen: Yeah. Like I said, great discussion. It's incredible. Roughly a decade ago, we were advocating for the single-arm trials to get agents. We have the agents. So I think this was one of those talks where it's exciting to look towards the future as we continue to parse out head-to-head data and really give our patients more feedback on what we think is our best option. Thanks for joining us again on UroToday.

Joshua Meeks: Great. Thanks again, Zach. Great to talk.