Managing High-Risk NMIBC
Transcript: The future of NMIBC trials
Joshua Meeks, MD, PhD
Recorded September 2025. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
Thinking about NMIBC trials and how to make them more patient-friendly, I think you really have to start with the end in mind. So the main things that people are concerned about are recurrence and trying to address that as a primary endpoint. So, you know, progression is obviously the most scary endpoint to someone, but recurrence is the one that they deal with the most. And I think the eligibility criteria and how these trials are set up are absolutely critical. So, you know, when you think about these incredibly strict timeframes about centralised path review, and unfortunately, some of that's driven by, you know, regulatory authorities as far as ensuring that someone's not a muscle-invasive cancer, for example, and so requiring centralised path review, you know, that takes time.
Time for centres to get the slides, get them cut, get them sent. If it's a big endoscopic resection, that's more slides, and so all that leads to patients sitting there waiting to go on trial, and ultimately their lack of satisfaction with the trial and concern from the provider. And their big reason for that is that many people, this is their first interaction with cancer. They really don't... This is not a life-threatening cancer where there's no other options. If you look at, for example, BCG-naive patients, they have BCG. You know, most people have a therapy in their closet that's very reasonable to be able to give and works incredibly well. So to say we should put that on hold while you come on a trial, that's a big ask. And so I think thinking about that upfront, about why would the patient be involved with this when there's a very good option that we've used for 50 years. I mean, that's one of the reasons why it's been very challenging to beat BCG. But I think making things very patient-friendly, as far as being able to come on trial, to receive therapy.
You know, I think, for example, when controls are chosen to compare experimental arm to, where the controls aren't necessarily the standard of care. For example, in the U.S., we have a non-FDA-approved therapy that's gemcitabine-docetaxel that we give as urologists. Patients do really well on that, but most of the time it's not gonna be selected as a standard of care because it's not FDA approved; it's not given, for example, in different private practises, it's often not given in different parts of Europe. But we know it's incredibly effective, and it's hard to convince a patient to not use that, to use a different standard of care that is potentially FDA approved. It just doesn't make sense. So I think thinking about what makes sense to the patient makes it very easy. I think the other thing to really think about is the role of surgery. For example, like ablative therapies where the patient has a tumour and can avoid a surgery. I think that's another important thing to think about. So, you know, again, just to summarise, I think having entry criteria that will allow the patient to go on trial, to receive therapy, therapies that are well tolerated, and, you know, are worth someone considering, you know, avoiding a very easy standard of care. I think just having that pragmatic approach is really what's needed to get patients to want to be involved in clinical trials. Again, we have good therapy.
So the question is, what are you really offering that's gonna be ultimately a benefit for the patient? The problem is that, you know, when you have a very restrictive trial, it tends to lead to a very homogeneous population, which is good from an analysis perspective. The more diversity you bring into a trial as far as past medical history, other comorbidities, other medical problems, the more probably heterogeneous the population is, and potentially other confounding things that come into it. So it's gonna make the trial larger. So I think, you know, you kind of have to think about what the goal is, you know? You're probably gonna have a larger population if you're gonna let other things in, but that's probably gonna ultimately lead to better applicability across the cohort. So that's kind of the thought about that. Again, you've got to like trials where there's less, like, tissue-based requirements, there's less, you know, strict criteria. For example, if someone has a history of prostate cancer, they are often not able to go on, even if they're on active surveillance, because it's another malignancy. Or for bladder cancer, for example, if they have a remote history of upper tract cancer and they've been treated for that, they can't go on. Or if it's a low-grade trial and they've had high-grade more than a year ago, even any high-grade cancer, they're not allowed to go on trial.
So, you know, again, I think all those criteria, while the goal... And you can see the way that the trial's designed, it makes a lot of sense, but the real challenge is you become very selective of the patients that you let in. And that may lead to, again, a homogeneous group of people being tested. If you think about it like an experiment, that's great, but that's ultimately not who these drugs are gonna go to treat. So I think most people are willing and interested, at least the folks that I see, you know, in the academic setting; they're willing to participate. But the trials can't be so onerous that it's not feasible. You know, again, like, if someone needs six hours of urine collection, that's their entire day to spend in the hospital, you know, urinating into a jar. So if they're gonna do that, you're gonna select a certain group of patients, and you're gonna have to compensate them, and it's gonna be very hard for most people to do that. So I just kind of think about, like, what would your family member be willing to do? That's sort of what I always think, is that like, if I would be willing to put a family member on this trial, would this be a good trial for them? And if it doesn't meet that criteria, then it's probably not something that we're gonna open here.
For BCG-naive patients, the primary outcome we usually look at is high-grade recurrence, and that's probably the best outcome we can look at. But I think when you look at, for example, BCG-unresponsive bladder cancer, the primary outcome that drives that field is how many patients achieve a complete response, so that percentage of complete responders. And that's a really challenging outcome because you can hit that complete response, and then it can go away in the next scope. Or that response can be based on a physician's, like, view of the bladder, but then all of a sudden, you know, when you have to do biopsies, that goes away. And that's, again, not every trial requires biopsies, or requires them at a different time, or some will allow reinduction if there's cancer present. So it's like you kind of get a mulligan on treatment. So I think that getting a response is important. Again, it's probably, you know, the part of the curve that tells you how effective a drug is. But realistically, for most people, the question is: how many people are gonna be cured? Or at least a year from now, how many people who started on the drug will be having a response? That's probably a more important question. So, that duration of response, if you had to pick one, I would say, especially for the BCG-unresponsive group, that's the biggest one. Again, when you look at things like how many people can avoid a cystectomy, I'm not sure that's fair. There are some patients that, from the very beginning, say they'll never do that. Or a lot of that's driven by the provider or the patient and their willingness. So I'm not sure that cystectomy avoidance is a very good outcome. I think for the intermediate-risk group, you know, that's usually recurrent low-grade cancers, you know, really, what drives that is recurrence, right? So how many people are gonna have their tumour come back? And that really does matter.
You know, the big challenge for those patients are they're usually very well. So, having any kind of toxicity is almost just as important as avoiding a low-grade recurrence. So again, I think every space, as you get into it, is a little more nuanced, and the outcomes that matter to each patient are different. Again, if you talk about patients with muscle-invasive disease, it's probably survival that matters. But as we move back to NMIBC and different parts of it, those goals, those endpoints, are gonna be very different. I love the idea of sort of a STAMPEDE-like design or a crossover design where a patient can enrol and then get randomised to a therapy. And then if that doesn't work, or they have toxicity, or they're not able to continue further, there's a backup, and there's another therapy; they can cross over to another arm. And again, the reason for that is that oftentimes when someone's been on one therapy, they can't go on another one that's experimental because their bladder's already seen one treatment, and they're excluded. But we know that, you know, trying to push the cancer sort of into remission, those might not always be durable remissions, but some will last longer than others, and for some people, they will get to cure it. But having sort of that comfort to "We're gonna start with drug A, you're gonna go on drug B, in the meantime, drug C may come into this," I think that kind of network of rotating options is really appealing to the patient. Because that means they're not gonna have to finish a trial and go on and either find a different group or consider a cystectomy. That you're sort of, "As long as you're being safe." And again, you're looking for progression at every time point, but you are saying that "We're gonna be with you for a while, and, you know, these are the options that we're gonna bring to the table as different treatment options." I just think that pragmatic approach looks at this as a longer landscape, rather than "We're interested in drug A. We're gonna do everything we can for drug A. But if drug A doesn't work for you, then I can't see you anymore, or I'm not interested in caring for you." I think the relationship we develop with our patients are much more of: "The trials, if they work for you, are great. But these are what we're offering, and these may be a good opportunity for you." But we're in for the long haul with our patients. So the trials have to be considerate of that. And anything that's so, like, one-drug-focused, I just don't think long-term ends up being a good win for the patient. Yeah, I mean, so there's a lot of work that we do in the NCTN, you know, in our national clinical trials network, where they're bigger frameworks. And probably for me, the best example I've seen is, you know, in lung there's a trial called Lung-MAP, which is a biomarker-driven trial. And it's basically started off as two to three arms, and then that's the framework of people coming in with, you know, advanced lung cancer, and then arms keep getting added, which facilitates these trials being opened and asking an important question. And so I think, you know, a lot of trial development is getting set up and getting the infrastructure of sites.
I mean, many trials just never get off the ground because it's hard to recruit sites. But if you have sites that you know are able to accrue and able to see patients with this cancer, that framework is there, you're just bringing in different opportunities for patients to participate. So I think, thinking about that, that that probably, again, is not gonna be an industry-run event. It's probably gonna be something that may be run better, you know, at the sort of, you know, government-level kind of infrastructure. But I just think that thinking about multiple different options for patients is probably gonna be the best answer. Many trials now, most of them, will have some version of patient-reported outcomes, and usually there are different satisfaction surveys with quality of life and voiding quality of life. I think realistically, that the ones... You know, again, what we've learned about that from a provider perspective is that if people are doing well on trial, in general, they tend to be more optimistic. There are some therapies, though, that are pretty rough for people to tolerate, and you just have to stop.
You know, and again, it's really not my expertise, I'll tell you my expertise as far as getting into, you know, prioritising different PRO mechanisms. I think they're important to look at. In general, they tend to be relatively stable across time. But the key thing that I see, again, more on the clinical side of it, is: what percentage of patients have to stop therapy because of the side effects? And if that number is significant and the patient can't tolerate it... And again, most people are pretty selected, they're pretty highly motivated. If they can't tolerate it, then that's an important outcome. Like, if they're not able to continue the therapy because of toxicity, I mean, that... That probably should be anticipated before then, but realistically, the ability to continue on therapy, to tolerate therapy, if people can't do it, then that really suggests that really doesn't matter how great the therapy is, that it's not something that's gonna move forward. I think the biggest thing you can do is have patients involved in the development process, right? So we all have... You know, there are certainly patient-run organisations that, you know, clearly are invested in this, and many of them have training for patient advocates that are involved in it. And I think that's been the biggest thing.
Again, if you don't have patient advocates involved in clinical trial design, they've not seen it, they've not been able to experience it, they've not been able to share their thoughts on it, I think you're really missing out. And so, you know, most, again, cooperative group trials that I've been a part of have heavy, heavy involvement from the patient advocate. And, you know, that's just the cornerstone of it. If it doesn't make sense, you could have the best scientific concept in the world, but if you can't get buy-in from your patient advocates to say that this is the right thing to do, that they could try to explain this to their friends and colleagues, then even as a provider, it's just not gonna work. So I think including the patient advocate as part of the team pretty early on from trial design, I think that's just sort of a foundational piece. Yeah, so, you know, many trials, you know, again, that come through the cooperative networks, they're open at, for example, different NCORP sites and community hospitals. They get some credit for that, and that's really important. I think having trials that, again, when you sort of take away a lot of the phase one, phase two, more of the scientific part of it, tends to be more able to go to a community-based setting. So I think that's really important, that some trials can do that. Now there's gonna be some that probably need to open up places where, for example, PKs can be done in a timely fashion. But in general, I think as the trials get bigger, they need to be more accessible. And again, probably more on the pragmatic side. We talk about pragmatic trials, and there's some criteria, but that's pretty loose. I think thinking about what can be done at most community hospitals, you really have to think about, you know, very simple designs, easy to carry out, very patient-friendly, all those are gonna be, you know, really important parts to trials. But trying to think about that as a primary design is really important. The real-world data that I've seen from for many NMIBC trials comes down to, you know, doses given, patient acceptance, real-world outcomes. And oftentimes that data is pretty close to what we see on trials, that are the bigger trials. But I think the real-world evidence data is what people are doing in practise.
And, you know, many of those are gonna be like higher-volume community sites. But that really informs us about, you know, if there's a big barrier between what's going on at certain academic settings and real-world settings, then that tells you that there's a problem that needs to be addressed. And again, some of that is access to certain medications. There are some drugs that are incredibly expensive, and even though the publications show a very high response rate, if the patients can't get them in the real world because of barriers with pre-authorization, drug delivery, you know, then it's just not feasible. So I think trying to think about what people are actually doing, you know, that sort of, again, goes with the end goal in mind. And if you don't address that, then you can have a great outcome that no one else can use. But again, that's sort of almost the last... Like, you have to go through an FDA approval for a therapy before you get it to the hands. But maybe starting to think about that from the very beginning is gonna shape the trials a little bit differently. Trials are incredibly expensive. And, you know, if you look at the gap that we had 10 years ago, it was that there were no drugs in the space. And so what changed is we allowed single-arm phase two trials, and that led to a number of approvals. We probably have four to five different therapies that have now been approved by regulatory authorities. But then the question becomes: do you need five therapies? And they're all very expensive. So what you'd wanna do is kind of what we just talked about as far as being able to compare them head-to-head to see not necessarily what's the best, because I don't think you need to have the best, but at least knowing about comparable toxicities and what may be better for certain people. You can't really do head-to-head therapies in that point. No one's really invested, like, you know, in doing that. So I think there's some optics in real-world challenges beginning to think about what drugs we actually use in patients, because we don't really know how they compare to each other.
So that's kind of become the next generation of taking the therapies that are approved and comparing them, or trying to do some comparative studies as far as people who are on these trials and who take these drugs in the real world, and what experiences they have. I think that's gonna be... You know, again, now we have some drugs that have come into the pipeline, but figuring out who best to use them with. Like, when you're sitting down with a patient and saying, "All right, I have drugs A through F," other than frequency of administration, the next question is toxicity. And so how do you compare those? And, you know, you see the reports, but really, until you're able to use all them, that's a challenge. So I think that's what we're gonna be dealing with for the next five to 10 years, is maybe some more drugs coming in, but we're hitting those benchmarks as far as efficacy. And so now it's gonna be what drug do you use at what time and what patient. Well, I think... So, the two things I would say that are gonna potentially change, now that we have, you know, a cabinet full of therapies, right? I think the next things that need to change are, number one, a little bit of comparison as far as getting to precision, as far as who needs what, who will do better with what drug, at what time point, and, you know, trying to pick which patients are gonna do well. And again, some of that may be a drug is given every two to three months versus six times a week. Well, if you live in the city and you're close, maybe every week may be fine, but if you live far away and you're, you know, more rural, then every two to three months may be better for you. That's just some geographic limitations. But specifically related to the cancer, we really don't know much about that right now. So there's some work that needs to be done there to try to align patient and therapy. I think the next part would be looking towards de-intensification.
Again, all these trials are sort of set up to hit the highest bar, to get the most response and the longest duration of response. But we don't know when we can de-escalate. I mean, to be fair, we don't really know that with BCG, right? That therapy's been around for 50 years. We don't know who needs multiple courses of induction. We don't know when we can stop maintenance. You know, having the shortage let us sort of figure out that a year is probably sufficient for many people, but not everybody. So I think thinking about de-intensification, which is really meant as a good outcome to try to decrease the burden of therapy, but it's very hard for patients, when they're having a response, to try to de-intensify if they're tolerating it well. And again, we hear that all the time with BCG, where people wanna continue on as long as they can because they're having a response.
The therapy ultimately really may not be doing anything for them at that point. It may just be that their cancer's gone. So, again, I think precision and de-intensification, you know, and risk stratification is probably the next phase of how to make our treatment of patients with NMIBC better.
Developed by EPG Health. This content has been developed independently of the sponsor, Pfizer, which has had no editorial input into the content. EPG Health received funding from the sponsor to help provide healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content. This content is intended for healthcare professionals only.
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