Managing High-Risk NMIBC
Transcript: The future of NMIBC treatment
Joshua Meeks, MD, PhD, and Ashish Kamat, MD, MBBS, FACS
Podcast recorded October 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.
- [Ashish] Hello everybody and welcome to the podcast series titled "Expert Voices: Navigating non-muscle-invasive bladder cancer." Today's episode is titled "Treatment challenges: Emerging options, and how they could change practise." I'm Ashish Kamat, urology oncologist in Houston, Texas, and for this topic we could think of no one better than Joshua Meeks, joining us from Chicago. Welcome, Joshua.
- [Joshua] Thanks, Ashish. Great to be here with you.
- [Ashish] So there's so much going on, right? I mean, the treatment landscape is changing. There's newer drugs that have been approved in BCG-unresponsive disease. There's trials going on in the BCG-naive space, high-risk non-muscle-invasive bladder cancer. There's trials that are read out, CREST, and some that are gonna read out, or be presented, at least, in the upcoming weeks at ESMO. So it's really a difficult topic to cover in 20 minutes, but I'm gonna have you attempt this, right? So first off, when you are sitting down with a patient in front of you, and let's talk about BCG-naive patients for now, how are you counselling them on the standard of care and what's coming down?
- [Joshua] Yeah, so I think for BCG-naive, you have to start with the known winner. So I always begin with BCG. It's pretty rare in 2025 that a patient is gonna be in front of me that's got, you know, a high-grade tumour that you know that, that's gonna get, or BCG, potentially like receiving, and they've never heard of BCG, don't know what it is. I still find maybe 20, 25% of people haven't heard of this tuberculosis vaccine that we're gonna put in their bladder. But many people, at this point, have some sense about what it is. So I always begin with BCG. And I don't know about you, but I talk about, like, this is our industry standard, you know, for now we think that this is the most effective. Now I start with that, talk about side effects, and then we say, "Listen, it wouldn't surprise me if in the next, you know, two to three years there's challenges to this," and this is kind of what's coming. I, obviously, we have chemotherapy options, gemcitabine/docetaxel. Because we have adequate BCG at our system, I'm able to give pretty, you know, I give reduced dose BCG, but I still am able to give BCG. But Gem/Doce, I don't usually give patients unless they have some contraindication. They've either, you know, had significant tuberculosis exposure, they're immunocompromised, you know, or they, they have some reason from another medical cause that they just can't get it. Now more and more people are asking me about molecular testing and I think we'll maybe may talk about some of the tests that are out there to help predict response to BCG. When people get interested, I ask, you know, we consider that for some of the AI testing, but I really, you know, my default for most patients are still BCG.
- [Ashish] You know, I'm glad you said that, Josh, because you know, there are a lot of people who look at BCG, and say, "Well, this therapy's been around for 40 years, why are you still recommending it to me?" And you know, my default is well because it works the best, right?
- Right, yeah.
- And the data now suggests that with better optical enhanced technology, better TURBT, better risk stratification of patients, the results are actually even better with BCG today than they were when they were first being or first being used for patients. So clearly it is the standard, but everyone's looking for ways to beat it. So tell me a little bit about your thoughts on the CREST data. CREST was when they looked at sasanlimab with BCG against BCG and the data that was presented and published showed that there was a benefit to adding the IO therapy to BCG induction and maintenance. Okay, with that background, go ahead, Josh.
- [Joshua] Yeah, but, and I realise, you know, there's still a couple trials out there with a similar trial design, different therapies, still using BCG as a core. They still have a BCG replacement arm in the maintenance setting. But I have to admit, Ashish, I was actually pretty surprised when I saw the results, and that's not a lack of faith in checkpoint therapy, but we really haven't seen, in bladder cancer by adding a checkpoint monotherapy that's improved clinical outcomes long term with durability. So we haven't seen that in the metastatic setting. You know, we began to see a little bit of that with NIAGARA, but that's obviously adding it to chemotherapy. So I have to admit, I had a lot of doubts about the results before I saw them, but you know, clearly there's an improvement in event-free survival for certainly for high risk patients, T1s, carcinoma in situ. I think the split on those curves are interesting the further out you get. So it's kind of weird, you know, when we talk, when I'm sitting in front of a patient and we get them to two years, I think about the recurrence risk as being very low. But that's really where those curves begin to split. So maybe that's where the checkpoint is adding a boost. I think, you know, it, it's not FDA-approved. We don't have that therapy where I'm able to give that to a patient today. But I definitely think it's gonna be part of the discussion about how do we add, you know, juice to the squeeze on your therapy. Is checkpoint the right thing for you? Here's the toxicity. Again, it's a very different toxicity profile to talk to a patient with metastatic cancer and talk to them about adding a checkpoint and here's your toxicities and that they're low, versus someone who could get BCG heavy. As you've shown 75 to 80% chance of cure. And we wanna make that better. So I think again, it's gonna be very, those are very nuanced discussions, and there's certainly people who would, are going to, you know, opt for that. But I just don't know that that's gonna be every single patient.
- [Ashish] Yeah, and, you know, the way to look at it is the event-free survival rates reported include recurrence, whether it's Ta recurrence or T1, we don't know, 'cause it's not substratified and also progression, right? And what matters to our patients is progression. So it's, let me ask you this. Let's assume that the upcoming trials at ESMO also read out positive. What would it take for you to use IO with BCG, and in which patient would you sort of say, "Well, hey, for you, I think this combination systemic immunotherapy fits into your treatment landscape."
- [Joshua] I mean, to be fair, Ashish, I really think that BCG does a really good job with the papillary, like the Ta high grades, right? I mean, you know, those patients do great. For them, the risk of progression is low. So I don't know that we have a lot missing in that space. I still think patients have a risk of death from bladder cancer, especially the Stage 1, right? So those are the ones that I worry the most about. I think if you see a benefit with Stage 1 where, again, with progression, and even though CREST showed a benefit for recurrence, there was no OS benefit, right? So I think if you, if we see an OS benefit, clearly that tells us that, and that just maybe number events is so rare for survival. But, but really to me, if you see a survival benefit, it's hard to argue with that, right? Like that locks in a huge difference. So the only alternative would be, you know, thinking about the downstream. But as we're gonna talk about, there's a lot in the BCG-unresponsive space where, you know, we used to not have anything. So it's like you don't respond to BCG and you're talking cystectomy, now, you know, we have a treasure of riches to talk to people about, where if this doesn't work, I've got second, third, fourth, fifth line. So recurrence doesn't bother me as much. It's the progression events, the metastasis, you know, to me, those are the ones where if you can show a benefit with adding checkpoint, which is kind of what we would hope, then I think that's a bigger, bigger deal. What about you?
- [Ashish] Yeah, it's hard, right? Because again, BCG does so well, and progression numbers are in the single digits, right? So the event rate is so small you can't really show a benefit. And I think that's the critical question for our patients. How can I actually help you, which is the patient, prevent a progression of your disease which actually matters. A recurrence, I could take care of, we could cauterise it, we can then come in with something. But progression is truly what what I'm worried about. So interesting to see what the data will show there. So again, you're a big believer in science, in doing what is appropriate for the patient based on the data. What do you think is gonna beat BCG? Do you think chemotherapy doublet combination, the BRIDGE trial, do you think that might beat BCG? Do you think the TAR-200 device head-to-head with BCG might beat it? Any crystal ball gazing there?
- [Joshua] Hmm. Well, you know, if you look at all the retrospective data on Gem/Doce, you know, it, I've yet to see any suggestion that it will not be successful in BRIDGE, right? Like everything we've seen so far retrospectively, and again, we thought that about lymph node dissection, but clearly, you know, my sense would be that it's likely gonna be non-inferior. And not only do we have those, not trials, but we have retrospective data with, you know, selected patients to suggest that. But we also have the real world experience of having patients get Gem/Doce in a setting where there is no BCG, and those patients don't seem to do any worse. It's not like, you know, we see a lot of those quote unquote "Gem/Doce failures" coming in for cystectomy or being referred for other treatments. So my sense is that that will likely be non-inferior and maybe some of that, Ashish, is gonna be tolerability. You know, one of the big challenges with BCG is we know if you go full dose, you know, there are people who are not gonna tolerate it. That's just part of the, I would say, the therapeutic window of it. So I definitely think Gem/Doce oncologically will be non-inferior. Will it be superior? Hard to predict unless it's based on tolerability, right? So that would be my prediction. What about you? What would you pick with BRIDGE if you were to guess?
- [Ashish] The issue there, I think, Josh, as you mentioned, is getting patients to three years with BCG, and we have a lot of tricks up our sleeve now to educate patients, dose reduce, et cetera. So I think that's less of a problem. But clearly, like you said, there's some patients who just can't tolerate immunotherapy, they have severe reaction, and in them the combination would be better. And of course the BCG shortage issue, which needs to be resolved, and we have to trust that it will be resolved by 2027.
- [Joshua] Yeah, yeah. - [Ashish] Switching gears a little bit, we've had another episode on BCG-unresponsive disease, so I don't want to necessarily take too much of your time there, but that is also where you have a lot of experience, right? With nadofaragene, with cretostimogene, with, clearly with IO therapies, with R-200 device. So if you could, in brief, kind of assume I'm a patient listening in, and you are guiding me through the different treatment options that exist right now, approved and available, and I have BCG-unresponsive T1 disease, and I'm refusing a cystectomy.
- [Joshua] Yeah, so I think you, you start with basic goals about where the patient is, where their bladder is, you know, what they feel like now. I mean, again, if someone's bladder is really, really miserable, I start with the discussion of is your bladder worth preserving, right? I think, you know, to be fair, like our therapies outside of, you know, outside of IO in this setting are all gonna go into the bladder. So if their bladder doesn't work well, if they're miserable because of their bladder, if they are just, you know, if it doesn't seem like there's any improvement on different treatments like anticholinergic or Botox or anything like that, I think cystectomy is not an unreasonable way to begin, right? But if their bladder works well, I usually start off with the be most experience that we have, which would probably be gemcitabine/docetaxel. I mean it's not FDA approved. It's, but I'll tell you, it's, you know, it developed from urologists like us going to their pharmacy and saying, what do we have that we can put in a bladder? And it actually works surprisingly well. So I mean, I quote people data that's, you know, 60-some percent chance that they'll be on this treatment at a year, probably in the 40 to 50% chance at two years. And, and most of those people will be cured, but it's two years of therapy. So I generally start with that and it's pretty similar for most people to BCG. Probably after that, we talk about nadofaragene, and the reason for that is the dosing and the efficacy. I mean, I think that's a very nice balance between the two of them. And I think it's very reasonable to talk to patients about that, especially when they're from far away. You know, after that, I think you're starting to talk about very nuanced discussions about ANKTIVA and adding ANKTIVA to BCG and this is another possibility, especially if they tolerated BCG well, that this may be another way to sort of get a little more squeeze out of the BCG. And then, you know, really the pembrolizumab, I kind of use that very exclusively in patients whose bladders don't work very well, or if they have, for example, upper tract disease that's carcinoma in situ and bladder cancer, or they just, you know, they're far, and they kind of wanna do something very different. So I put those on the table, that's what we have available to us now. Where will TAR-200 fit into that? Again, it'll be very interesting efficacy-wise, obviously the numbers are outstanding. So my sense is that that will probably move up very, very high and may, it may be a competitor to Gem/Doce. I think, you know, as we see patients going through the approval processes to be able to receive it, that may be something that we have to kind of figure out institution to institution, but it's right up there. And so I think that's gonna be something that we'll be bringing up to the forefront, 'cause you kind of want to go with your best gun first. And again, that the response data on that is so high that I think that's one that certainly deserves merit.
- [Ashish] Yeah, and, you know, as part of our effort through the IBCG, clearly, you know, to try and help patients on a global scale as far as cost and access is concerned, we did a cost analysis, which is in press right now at European Urology. And we found that in patients who want to try something and don't mind trying an off-label combination, gemcitabine/docetaxel is the most cost effective, right? And then, if patients say, well, we wanna try two lines of therapy, then nothing is cost-effective, a radical cystectomy is cost effective, right? So the pricing of these drugs is something that clearly has to be factored in when it comes to access. And I wanted to ask you, and I know you're in a university setting, sort of similar to us in the cancer setting. We have the luxury of not having to worry that much about it, but still, if you could shed some light on, you know, to our audience listening, what do you think are some of the barriers would be as far as cost of these drugs, access, those sorts of things with all these novel therapies?
- [Joshua] No, Ashish, I really, I hear you and it even, we are in a setting like that, but I'll tell you, it's, we're currently not giving it in, we're building towards giving it in our infusion centre, but our infusion centre is not set up to give urologic therapies. I think from our clinic perspective, you know, it's a lot for an individual clinic to put into the budget of a single dose, for example. That can be, you know, almost, you know, a small percentage of the entire budget for the year for one dose of one of these therapies. So it's almost one, you know, one patient gets a therapy, then you wait for reimbursement. So again, I just think that that's a very challenging thing for individual clinics that aren't covered in that way to really manage it. So we've been navigating that, but I think that's a question that's gotta be addressed because all of these therapies come in and the price is high. Now, I don't know how that gets managed, because, you know, clearly I don't know the reason for the cost, my assumption is that a lot of that is production, R&D. But if you look at other forms of medical care, for example, in different biologics used in GI and dermatology, the costs are still there, but they find a way to provide access to patients. But for now, I think, I think us, as urologists, are trying to manage that cost world where we've really not had to do that yet. So I still think there's a lot of learning and a lot of build out that's gonna happen. And probably adstiladrin was the first one in there and next, ANKTIVA. So it's one of these things that's, it's not going away that we're trying to, every institution is gonna have to figure that out because it's gonna be different at every place.
- [Ashish] Yeah, and, you know, when we have to be practical, good stewards of healthcare dollars, we're dealing with patients with more risky disease such as high risk disease or BCG-unresponsive disease, that's one issue, right? We're willing to go to bat and say the cost might be justified, but then that brings us to the intermediate risk space with non-muscle-invasive bladder cancer. And I know we could have a whole separate podcast actually, but I wanna pick your brain on a couple things because I know you've been a good strong advocate of deescalation of therapy in those patients too, right? Though some may not need anything, may just be able to be observed for up to a year or two years. On the other hand, we have a lot of these trials with, for example, cretostimogene and nadofaragene, going in those spaces, the intermediate risk cancer. Without asking you to, you know, be too provocative, although I'm sure you will be, what are your thoughts there? Where do you think these agents and drugs are gonna land in the intermediate risk space?
- [Joshua] Well, you know, it's a very interesting group of patients. My experience with most of the patients I see here in Chicago for intermediate risk are usually very well patients with, for the most part, relatively minimal medical problems. And this is a major thing in their life that they're trying to work through. I think that's a different person than someone, for example, who has BCG-unresponsive disease in general, who tends to have other medical comorbidities, and this is, that's one part of it. The reason I bring that up is that their perspective on this cancer is that it's something that they're usually inclined to do everything they can to fight, but realising that they're well. So our therapies, the toxicity profile cannot be high for these patients, because, like you say, they're not gonna, you know, they're not gonna die of this cancer. That primary endpoint is recurrence, it's not death. But at the same time, you know, their goals are to be cancer-free. So I think it's part of the discussion. A lot of times, for example, when we were thinking about chemotherapy versus observation and office-based fulguration, you know, all the toxicity of chemotherapy just doesn't add up. The intravesical therapies we use that, you know, the, it's not like you're trading a hundred percent efficacy and you're willing to tolerate that. The efficacy of those therapies are not great, which is why there's a good window of therapy there. But that's been my experience with most patients is that I think there's gonna be treatment that it's gotta be incredibly well-tolerated with minimal side effects, and the efficacy profile has to be high enough that, you know, that patients are willing to do that. 'Cause this, it's not like I, you know, it'll be interesting to see what the long-term date is. I think we're gonna get oncologic wins in the short term, but long-term, really very interesting to see how many of those patients have true cures and don't have like small papillary low grade recurrences.
- [Ashish] Josh, always a pleasure chatting with you. I know we're coming up on time, but I'm gonna ask you one last question because you really lead the field in this area. Emerging diagnostics, molecular profiling. What impact do you think these tools are gonna have on our ability to offer truly personalised therapy to our patients?
- [Joshua] I think for, you know, in this space, in the NMIBC space, really you're in tumour DNA, I think the negative predictive value is gonna be incredibly powerful. So if you're, you know, because of the cancer field changes that we see, having a negative MRD or a negative assay, it is gonna be a pretty clean outcome that I think we can, or my hope is we can safely deintensify. Now can you intensify that? I'm not sure. My sense is that probably on the flip side, ctDNA may be the intensification that we can use. We know, you know, somewhere between 35 to 40% of patients with Stage 1 cancer have positive ctDNA, they probably should be intensified or at least have greater surveillance. But I really would hope for our folks that a negative urine test could potentially allow us to stop therapy, decrease evaluation, or even maybe replace some of the endoscopy that we do. So that's kind of what I'm hoping that we'll see in the next year to two.
- [Ashish] Yeah, no, I mean, that's an emerging field, right? And again, everyone's focusing on the latest molecular urine test. But just a little plea to our audience that is listening that may not have access to it, don't forget cytology. You have cytology today. Don't forget to get it. It's an important tool available. Josh, always a pleasure. We're coming up on time, so we're gonna call it. But thanks so much for taking the time and joining us.
- [Joshua] Great to talk, Ashish. Thanks again.
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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