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Ashish Kamat: Hello everybody and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center, and it's a pleasure to welcome to the forum Professor Felix Guerrero-Ramos from Madrid, Spain, who's joining us today to talk about his most recent work and also the publication in European Urology, which is based on and titled "Novel Delivery Systems and Approaches to the Treatment of Non-muscle-invasive Bladder Cancer." Felix, thank you for taking the time and for joining us today. The stage is yours.

Felix Guerrero-Ramos: Thank you, Ashish. Thank you, UroToday, for the invitation. I'm very glad to be here and to present the latest data from our review published in European Urology Oncology. Ashish is one of the co-authors of these publications, so he knows it very well. Basically, we try to provide an overview of all the new therapies that are being developed for non-muscle-invasive bladder cancer, including all the risk stages of non-muscle-invasive bladder cancer, and also with a main focus on intravesical therapies, but not limited to them, as we provide some context also for comparisons with systemic therapies.

We try to gather all the information from all the completed clinical trials, all those clinical trials that are still ongoing, whether or not they have preliminary results. We also added some retrospective evidence to put in context some of the new prospective data, and we also provide some future management algorithms. So it's a long article. To make it easier and shorter, we're just going to see some of the slides of every risk category, the evidence behind them, and maybe some of the conclusions or suggestions we have for these patients.

If we go to the most crowded scenario, which is the BCG unresponsive non-muscle-invasive bladder cancer scenario, up to date, we have three approvals by the FDA, which are for CIS with or without papillary disease; there is currently no approval for papillary-only disease. So the first approval was pembrolizumab administered intravenously, with a complete response rate, as you can see here, of 41% at three months. The second approval was nadofaragene firadenovec barely one year later, which reported a complete response rate of 53.4% at three months. More recently, the combination of BCG plus N-803, you can see here ANKTIVA, has a complete response rate of 71% at any time, which is much higher than the previously reported. And here you can see all the other complete response rates of the new alternatives, which have reported preliminary results. Here the main advantage for the intravesical delivery method is that the grade 3 or higher adverse event rate is much more favorable for those intravesical therapies while having at least the same efficacy as the intravenous therapies like Pembro or atezolizumab, which was not approved for this population. Always, we have the limit that we cannot make comparisons across trials.

If we go to the papillary-only disease without CIS, as previously said, there are no approvals for this population, but the results and the efficacy outcomes are much better. Here, we do not measure complete response, as the disease has been resected before the therapy, and this is more an adjuvant therapy. So we measure recurrence-free survival, high-grade recurrence-free survival rates, and we can see that, generally, these rates are better, are increased in the papillary-only disease population versus the CIS population. Again, to highlight that there are no approvals for this population.

If we move now to the BCG naïve high-risk non-muscle-invasive bladder cancer, there are some big phase III trials assessing the effect or the benefit of new alternatives, most of them with intravenous or systemic immunotherapy. We can see all of them here, the first four trials. The main difference between them is the way of administration of the immune checkpoint inhibitor, which, for example, for CREST with sasanlimab is subcutaneous instead of intravenous as in the rest of the trials. For example, the main design for these trials comprises a control arm with BCG induction plus maintenance from one to two years, and then an immune checkpoint inhibitor plus BCG induction or another arm with BCG induction plus maintenance with the immune checkpoint inhibitor, except for the ALBAN trial where there's only an interventional arm with atezolizumab plus BCG for one year.

We can see that there are also several differences regarding the BCG strains used in the trials. The number of patients is similar. It's around 1000, except for the ALBAN trial with only 500 patients, but remember, only two arms, and there are no reported results for these trials. There are reported results for the BladderGATE trial, which is a trial we conducted in our center. It's a phase Ib/II trial, one-armed trial for patients receiving atezolizumab plus BCG, both of them for one year. At the EAU Congress, we reported a high-grade bladder recurrence-free survival of around 87% at two years. But these data are preliminary, and it's a small trial with around 37 patients.

Then we have two new approaches for this population, the SunRISe-3 trial and the BRIDGE trial. For the SunRISe-3 trial, this is the first trial comprising an immune checkpoint inhibitor with an integrational arm not using an immune checkpoint. So we compare BCG induction plus maintenance for two years up to three years according to the investigator's decision. And there is an arm with intravenous cetrelimab plus TAR-200 versus TAR-200 alone. Again, around 1000 patients and still waiting for results. And then the BRIDGE trial. After certain retrospective promising data of the combination of sequential gemcitabine/docetaxel administered intra, there's currently an ongoing phase III trial comparing this approach versus BCG induction plus maintenance for three years. Again, no results yet. Waiting for them until around October 2030.

Finally, the intermediate-risk scenario has two main approaches for the new trials. One of the approaches is the classical one with adjuvant therapy trying to substitute or to increase the results of BCG or chemotherapy given after TURBT. The other approach is an ablative approach where we try to avoid TURBTs, especially for those highly-recurrent patients with more than one recurrence per year, aiming to achieve good complete rates, but also significant recurrence-free survival rates. And by that way, although if we compare costs, maybe saving TURBTs in these patients can be cost-effective and make savings for the healthcare system. So here you can see, in the horizontal line, all the current management of intermediate-risk non-muscle-invasive bladder cancer with TURBT plus postoperative chemotherapy considering adjuvant therapy according to the IBCG subgrouping of intermediate risk, which, by the way, has been recently validated. And then there is the follow-up.

So if we try for some ablative approach, we could have two options: administering mitomycin gel with UGN-102 or 103, which is an improved version, and if there's a complete response, yes, follow-up. We could also try to integrate some kind of personalized medicine approach looking for FGFR alterations. If they're positive, we can use an intravesical device, which is TAR-210 that contains erdafitinib. This is a targeted drug for FGFR mutations or fusions. If there's a complete response, we would just go for follow-up. But then we could also have some negative screening or no complete response with either treatment and then go to the classical way, which is TURBT plus postoperative chemotherapy or even consider a different ablative approach if the previous one has not worked.

Also, for those patients with adjuvant therapies, we know that trials with chemohyperthermia like HIVEC-I and II were negative, probably with some design problems and one of the studies being underpowered. But new options like adjuvant CG0070, which has shown very promising results in the BCG unresponsive setting, have also presented some evidence for these intermediate-risk patients and could be another adjuvant option in the future.
Finally, just thank you everybody for your attention. And now, Ashish, if it's okay with you, we can discuss whatever you'd like.

Ashish Kamat: Absolutely. Thank you so much, Felix. That was a very nice succinct summary. With so much going on in the field with non-muscle-invasive bladder cancer, the one question that people always ask me, and I'll ask you this, is what are you most excited about when it comes to, let's talk about the BCG unresponsive? Which therapies or class of drugs do you think is going to be the winner? Do you think there's going to be one winner, first of all? And if so, which one do you think and which one are you most excited about?

Felix Guerrero-Ramos: Well, there's a big bias here. Both of us are urologists. This bias, I think, could be managed because if we see the preliminary results of everything we have, I would say the winner is intravesical. And inside all the intravesical, for me, the most attractive drugs are maybe N-803 plus BCG with that 71% complete response rate. There are very nice lines regarding the recurrence-free survival, which are quite plain and do not fall. And also for me, the TAR-200 because of the way of working, the mechanism of action where you can provide a drug constantly with 24-hour delivery inside the bladder with these kinds of devices. For me, it's very promising not only in the BCG unresponsive but also in the rest of the settings of this disease.

Ashish Kamat: Yeah, no, I tend to agree with you. Something that allows us to give the patients local therapy rather than systemic toxicity will be, obviously, preferred by our patients and us. And then that brings me to the BCG naïve setting, where there are systemic drugs in combination with BCG, for the most part, trying to beat BCG. Again, BCG is so effective. What are your thoughts on whether these drugs or these combinations will, A, be successful, and B, how much better would they have to be than BCG for you to recommend them to your patients?

Felix Guerrero-Ramos: Well, first of all, BCG is difficult to beat. We know that we have some data of maybe old data where we have poor oncological outcomes for BCG, but we see that if you administer BCG correctly, you do maintenance, you resect the tumors well, you do ReTURBT, then BCG's oncological outcomes can increase and can be better.

There are two main drawbacks of these new drugs which are being tested in the phase III trials. Number one is the toxicity. We know that these drugs have around 14-18% of grade 3 or high adverse events in otherwise healthy patients. I mean, these are not some metastatic patients or second line. These are patients who are otherwise healthy, and sometimes they don't even understand why they do need treatment after TURBT because they feel well, they do not have hematuria anymore, and they say, "Okay, if my tumor has been resected, why do I need this?" And some of these toxicities can be lifelong. Maybe you can have some immune-related toxicity against the liver or lungs or kidneys or whatever, and that patient will be conditioned forever with this toxicity.

Number two is the cost of these drugs and if they show efficacy outcomes better than BCG, if these drugs will be for every high-risk non-muscle-invasive bladder cancer patient. I think we should select some subgroups of these patients, maybe those very high-risk patients, which are also included in the trials and for whom the guidelines recommend upfront radical cystectomy, but many of them undergo BCG. I would target if we show that in this subgroup these drugs are much better.

Ashish Kamat: Yeah, and of course we're all waiting for some molecular signature that will help us predict or prognosticate or allocate the drugs to the appropriate patient because currently we don't have anything like that. But we're all waiting for some signature to be developed, and I know your group and our group, we're all working on it.

Lastly, to talk about the intermediate-risk patients. Again, I love that figure. You and I discussed it several times. It's a really good figure, helps people think about it. So I'm not going to ask you too much about the drugs or the mechanism, but just a philosophical question. For patients that have low-grade disease that recurs, do you think that all patients need to have an intensification of therapy, or do you think there are some patients that we should actually be saying, "Hey, let's just observe, let's do active surveillance?"

Felix Guerrero-Ramos: Well, for sure. There are several criteria to decide what to do for your patients, but, of course, some elderly patients who are asymptomatic and you diagnose their recurrence in a control cystoscopy or whatever and they're not being bothered by the disease, they have always had low-grade tumors, if you have two tiny lesions, for example, we usually do that. You can just wait, do some kind of watchful waiting, and if the patient comes with hematuria or any symptoms or even some anxiety or whatever, then you can do TURBT for these patients. Not only for elderly patients, but some younger patients who are maybe undergoing one or two TURBTs per year, they tell you or they ask you, "Hey, it's only four millimeters, can we just wait? I don't want to stop working. I want to wait. So let's meet again in three months and see if it's feasible."

So I think there is a role for these patients, and in my opinion, for these new ablative approaches, it will be key, as I said, not only the complete response rate, which looks comparable to TURBT with the limitation that the control arm of this TURBT does not usually have adjuvant therapy. So it's a suboptimal management for these patients. If they demonstrate that they're cost-effective for the complete response rate, I think they will have a role here, and they will especially have a more important role if they also show better recurrence-free survival time so that you delay or avoid posterior TURBTs in these patients. But for sure, currently, with the things and everything we have to manage these patients, there is a clear role for surveillance or watchful waiting or however you want to call it.

Ashish Kamat: Felix, you were very clear in your presentation, but could I have you pull up the slide on the BCG unresponsive drugs from your talk? Because, again, our audience is global and some of the people that get this newsletter and the video don't have access to the full paper. So I just want to highlight one thing for our audience so there's no misconception among people. If you could just pull that up, we'll go through it really briefly before we end.

Felix Guerrero-Ramos: Here it is.

Ashish Kamat: Yes, exactly. So you were very clear, and I just want to highlight for our audience that when Felix, or Dr. Guerrero-Ramos, was talking about the 12-month numbers, the FDA recommendation or the guidelines were 50% and then 30% absolute. And those numbers there, 46, 48, 45, those are relative. So those are 46% of the 41, 48.9% of the 43. Again, you were very clear, Felix, but I just wanted to make that clear to our audience who may not have access to the full paper.

Felix Guerrero-Ramos: Yeah, it's true. And the graphs in the publications, both for Pembro and nadofaragene, which were the first ones, the baseline, the theoretical 100% comprises only those responders at three months. So it's 46% of the initial responders.

Ashish Kamat: Right. And again, just to emphasize that, because I have been to places where people have thought that it's 46% absolute at 12 months, and that's not the case because obviously that would mean then the response gets better, which it would not happen, right?

Felix Guerrero-Ramos: Yep.

Ashish Kamat: So Felix, thank you once again for taking the time. This was very, very useful. Really appreciate it and looking forward to seeing you soon.

Felix Guerrero-Ramos: Thanks for the invitation. Looking forward to another opportunity for this. Thank you very much.