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Ashish Kamat: Hello, everyone, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and it's a distinct pleasure to welcome once again to the forum Associate Professor David D'Andrea, who is joining us today from Vienna. And he's going to talk to us about something that's very, very important for us to all recognize and learn about, which is essentially the cost-effectiveness analyses of the different treatment options.

David is a member of the international bladder cancer group, and he led this effort amongst a multicenter and multi-author endeavor. And David, thank you so much for taking the time and enlightening us today.

David D'Andrea: Thank you for having me. And it's a great pleasure to be here with you today. So we are quite lucky in this era because we are living a very important transformation in the treatment of urothelial cancer, and especially in the field of non-muscle-invasive bladder cancer. We have seen in the past years the development of several new drugs and treatments and, how to say, administration modalities of these new drugs.

And this led to a plethora of new studies and a broad field of new options that we have in these patients. So there was quite a need of summarizing all these treatment options that we have, also for counseling our patients. And this motivated us to conduct this systematic review and cost-effectiveness analysis on patients failing BCG treatment.

So the work that we did was based on two main points. First, we reviewed the literature starting in 1998 to 2024 to find studies that investigated other options in patients failing BCG treatments other than radical cystectomy. And what we found were—20, sorry—57 trials that investigated new drugs in these fields. And our systematic review comprised 68 study arms with 2,500 patients.

What we found was a plethora of studies and a huge heterogeneity in the study design, in the drug administration, but also in the population included. So the literature was quite a bit blurry until the FDA came up with a definition and set the endpoints for new drugs, which cleared the field a little bit. And since that point, now, we have better trials that we could, at least, let's say, compare the drugs among.

Here in this slide, I have summarized the most relevant studies that have been published in this era. And as we can see and as our systematic review shows, the primary endpoint of these trials was mainly the three-month complete response rate in these patients, which was fairly good. So we have roughly around a 50% response across all the trials, which declines a little bit after one year and gets almost blurry, or we have no good data in the long run, which is very important also for the next step, which would be our cost-effectiveness analysis.

The adverse event rates were around what we also see for the BCG-treated patients, so it's below 20%. And then after conducting this systematic review, we included only the trials which investigated drugs that are now FDA approved and compared it to radical cystectomy. And on this table, you pretty much see the quintessential of the analysis that we conducted. In this table, you see all the information is important to—yeah, in this analysis.

Let's go quickly through. So you see on the left the radical cystectomy, which was our comparator, so we compared the costs and the quality of patients treated with radical cystectomy after failing BCG treatment. We built this on a Markov model and included all the possible scenarios that patients would go through with the drugs that nowadays are available. And then we simulated this for the nadofaragene firadenovec, for the nagopendekin alpha and inbakicept, and for the pembrolizumab-treated patients.

The first thing that we can see is that the QALYs were much higher for all the treatments, with nadofaragene firadenovec being the drug achieving the highest QALYs in this population. Then we see the incremental cost, which, of course, from a certain point of view, is higher than that of radical cystectomy. And for the pembrolizumab, it was lower. But here, I want to point out this was only because in the publication the patients were treated for four months, so the cycles were quite short.

The incremental net monetary benefits, which we can see, were the highest for the nadofaragene and the lowest for the pembrolizumab. And the incremental cost-effectiveness ratio, which is also very important: we see nadofaragene had an ICER of 10,000, nagopendekin of 44,000. But pembrolizumab dominates, which means that there was a strong dominance for this strategy, meaning it was less expensive and more effective than treating patients with radical cystectomy.

And then we have the total cost of the two-year treatment. So in radical cystectomy, we have around 124,000 USD for the two-year treatment period. And we compare it with the others, so we have almost half a million for nadofaragene and nagopendekin, and 55,000 for the pembrolizumab. And lastly, the qualities of the different treatments. We see for the radical cystectomy, we have around the quality of almost five. But we have a huge improvement in the bladder-sparing treatments, especially for the nadofaragene firadenovec–treated patients.

So I just now come to my conclusions and some take-home messages for the audience. What we have to keep in mind are the limitations of the cost-effectiveness analysis in this scenario, as we only have data up to two years in the recent published trials, so we have some data uncertainty. And also the generalizability issues have to be kept in mind. And these Markov models, of course, tend to simplify complexities. So we cannot account for all the possible scenarios that will occur in, let's say, 0.1% of the population.

For the administration of these drugs, we have some regulatory barriers. So they're FDA approved, but not EMA. So in Europe, we are struggling to get these drugs for our patients. We cannot administer some of those in compassionate use, but we have also ethical limitations for some of them, and we cannot access them in several countries in Europe. When treating patients, we always have to balance the efficacy, the cost, and the quality of life in these patients. What our analysis showed is that we can definitely improve the quality of life of our patients if we treat them with these new drugs that are available.

And lastly, what is probably the most important thing is the multidisciplinary approach in treating patients with non-muscle-invasive bladder cancer in BCG. So you need a collaborative [INAUDIBLE] and team. You have to ensure communication with this team. And if you want to go for personalized treatments, this is, indeed, the most important thing. So I went very fast through this huge effort that we all did, and I'm happy to take any questions.

Ashish Kamat: Thanks so much, David. If you could go back one slide, and let's have that up on the screen while we're going through the discussion. Again, this is a rather Herculean effort, and you put a lot of effort into this, and you led the team in going through these analyses. One of the things that we always look at when we're looking at cost-effective analysis, we're looking at it from a population standpoint as far as health care systems.

And then we're looking at it from an individual-patient perspective.So for someone that's looking at this, for example, let's assume you're in your clinic, and you have a patient in front of you, and the patient is young, healthy, and let's say, in their early 60s. Relatively young for bladder cancer, but in early 60s, and you're using this data to counsel the patient. How would you use this data in a practical standpoint to counsel the patient as to the pros and cons, the cost, the effectiveness of these different agents that you study?

David D'Andrea: Yeah. Thanks for asking this. It's indeed the most important question that you're asking, and this is also why we did this analysis. So basically, what we found is that these drugs have good efficacy on the short run. On the long run, we actually do not really know because we have only limited data in some fields up to five years. But basically, this is why we limited our analysis to these two-year costs.

What we have to take into account here—because some of the audience seeing this data might get scared about these high costs that come with these drugs—is the most important thing that you have to keep in mind when interpreting cost-effectiveness analysis is that you're not using only the single drug. So you are comparing a strategy treatment. So in the patients who get radical cystectomy, in the two years after radical cystectomy, these patients will have some other treatments, they will have a recurrence, they will have metastasis. And so they will have also other systemic treatments. They have complications of the treatments. And all these come into account in this analysis.

And this also goes for the other three drugs that we investigated. So this is not only comparing one drug with radical cystectomy, but what happens with the patients within these two years. So when we use this data in our daily practice, we can tell the patients that they have a good chance to respond initially to the treatment, that they will have an enhanced quality of life. So they will preserve the bladder for the time they're being treated. What we do not know is if they fail this first type of treatment, can we give them then a second one?

So for example, failing nadofaragene firadenovec, can we go then with pembrolizumab, for example? We unfortunately do not have this data. But what is encouraging is that this data shows that patients who are treated with these alternative or, let's say, conservative drugs and not radical cystectomy have a higher quality of life. And apparently, in the short run, we showed this does not compromise their overall survival. Still, we need longer follow-up in these patients and longer treatment to confirm these assumptions.

Ashish Kamat: And the point, obviously, that you raised, I want to emphasize a little bit is that this is based on trial-reported data. So the trial will report obviously the best outcomes of patients that are selected, whereas for radical cystectomy, you're looking at real-world data, and you're looking at all comers. So that's one thing to keep in mind. The other thing is, yes, you absolutely don't know from this, and nobody can know what the cost or effectiveness is of a patient that doesn't want radical cystectomy, tries, for example, pembro, then says, well, I want to go and try something else. So how does that factor in?

And those are things that we have to caution our patients a little bit about because we don't know. I mean, we have some real-world experience, but we don't know from published data as of now at least. And again, you can do all sorts of modeling. I want to bring you back to this because, again, like I said, patients nowadays are very well read. They listen to podcasts or UroToday, and they come in with this information.

So if a patient comes to you and says—or comes to me, for example—and says, oh, I saw this great thing on UroToday. And according to Dr. D'Andrea, nadofaragene gives me a quality of 41. So that's the best treatment that I can get. What would your response and caution be as to what does quality mean when you're counseling a patient? And can they just go by that one number and say, that's the best treatment?

David D'Andrea: Yeah, absolutely. This is also a very important question. And basically, you already gave some answer before. So the data that we have, they are only from prospective phase II trials. We do not know how these drugs behave, let's say, yeah, behave or what the data are in the real-world scenario. So when we counsel our patients, we have to be very cautious about this. And the qualities in this scenario are numbers that come from the analysis that we have within the trials. So as you said, the patients that are within these phase II trials tend to be healthier and, in general, in better condition than the broad spectrum of patients that we have that fail BCG and will undergo radical cystectomy.

So when we counsel the patients and the patients say, oh, wow, the nadofaragene has almost three times the quality of life—gives me almost three times the quality of life—than other treatments or 10 times the quality of life than radical cystectomy, we can say, yes, because you can preserve the bladder, but you have to be very cautious, and we need more long-term data. And see also how these drugs in our clinic, when we use them on a daily basis, how they will be. And so further analysis, further data, are definitely needed in the future for better counseling our patients.

Ashish Kamat: Absolutely now. But I think this effort is very important because it opens people's eyes to the amount of cost incurred. Obviously, the quality of life is very important. Patient reported outcomes are clearly important. And again, you know this, and you're obviously going to be an integral part of it, but the IBCG has launched a patient-centric center that will be addressing a lot of these issues. Again, in partnership with UroToday, partnership with folks like yourself. So really looking forward to ongoing collaborations. And once again, thank you so much for taking the time and congratulations on the publication.

David D'Andrea: Thank you for having me, and thank you for your time.