Read the Full Video Transcript

Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology from MD Anderson Cancer Center, and it's a distinct pleasure to welcome once again to this forum, Professor Morgan Rouprêt, who's not only a dear friend but a true expert in everything urologic oncology, but specifically today, bladder cancer. Professor Morgan Rouprêt comes to us all the way from Paris, France where he is actually in the middle of a congress right now. So Morgan, thank you for taking the time and let's get started.

Morgan Rouprêt: Yeah, I'm super happy. Thank you again for giving me the opportunity to speak about bladder cancer, but specifically non-muscle-invasive bladder cancer because it's very rare, indeed, that we have, I would say, meaningful information to take out from such a big congress as ESMO. It is true also that there was some breaking news about metastatic urethral cancer, but what we want to focus on as urologists, speaking in our daily practice, what we are seeing is a lot of patients suffering from non-muscle-invasive bladder cancer, and there was some information.

On top of that, we start from the beginning because we want to split bladder cancer as it is now, and it is true that we have two distinct diseases: the high-grade disease where the blurred lines between muscle-invasive and high-grade bladder cancer are very difficult to delineate and we need to speak about the micrometastatic phenomenon, and there is the group of the low-grade where it is very specific. We would like to work on a de-intensification of the follow-up and the treatment. And these two entities were specifically highlighted during the ESMO.

So the first thing I would like to speak on is the refractory disease, and we are all aware of the unmet need in the field, especially in the field of high-risk, non-muscle-invasive bladder cancer, recurrent after BCG treatments. We all know that there are small discrepancies between the definition that we could use from time to time in the U.S. and in Europe, and the urologists were not really involved in clinical research in that field before, so at the beginning, the first trials were difficult to recruit according to the inclusion criteria, but now we are in a way where we are more and more flexible and we have more and more options for patients after BCG.


The FDA has approved pembrolizumab after the KEYNOTE-057 as a systemic treatment in refractory patients. So what do we have from ESMO is the THOR-2 cohort, which was presented by Jim Catto. And it's very interesting because it's oral erdafitinib and it's targeted therapy because it's based on the existence of FGFR mutation. So it is something very specific. It's not a broad treatment that you are going to give to every patient. You have to make a selection before then, and we all know that erdafitinib is an FGFR inhibitor, which has demonstrated efficacy in FGFR-altered advanced and metastatic patients. But from the data that we have in ESMO, it's very promising as well in the localized disease.


So this is the design of the THOR-2 Cohort 1, where you can see that the patients were split within the experimental arm or at investigator choice the use of intravesical chemotherapy.


So these are the first randomized data ever published and released. And so the definition we just talked about, this is the definition which was used during the trial, the characteristic of the population is nothing really surprising in terms of age, proportion of the male, and you can see the group were roughly 50 patients in the erdafitinib group and twenty-four patients for chemotherapy, and the geographic catchment areas are North America, Europe, Asia, and South America. So a real worldwide study.


The curve is speaking for itself in terms of recurrence-free survival. The experimental arm is sticking with a hazard ratio, which is very impressive. So it's clear that there was a huge impact on RFS in the use of erdafitinib versus intravesical chemotherapy.


The only problem and drawback that we have, the forest plot is very demonstrative, is the potential toxicity of the drug, because it's an oral drug.


And we come back to the debate, maybe, that we'll have after the presentation is whether or not we should go for the intravesical route or the systemic route or both in the treatment of localized disease, but it's being dishonest to neglect the safety profile of erdafitinib, and we are facing a situation where there are some side effects that we need to be able to overcome or to discuss with the medical oncologist, but it is a reality and we cannot neglect this fact.


So there is a takeaway. There is room for targeted therapy in the NMIBC population, and probably this study is opening the Pandora's box of the fact that we need to widen the use of biomarkers in testing this patient with non-muscle-invasive bladder cancer because for many, many years we have been selecting patients based on clinical criteria or pathological assessment. It's far from being enough.


On top of that, I would like to make the transition to what is next in the pipeline, which has been discussed already. So in the intravesical route, we have the famous, I would say, pretzel trials that are under the umbrella of Janssen with the use of TAR-200, delivering chemotherapy within the bladder; or TAR-210, which has the possibility to deliver erdafitinib within the bladder at this time, which has nothing to do with the THOR cohort.


We are opening now, and I'm running all over the world, patients who are naive from BCG in a high-risk group. For instance, the SunRISe-3 cohort is actually enrolling, and there were some discussions around that at the ESMO, so we need to follow up on that.


But what was interesting is to focus a little bit on the low-risk category.


There are general considerations that we should take into account. It's not a small population when you look at the epidemiology, for instance in the US or in France. And the standard treatment so far is TURBT followed by adjuvant instillation of mitomycin.


There was at ESMO also a very important discussion about the concept of chemoablation. So you can see that from this phase one study with Cohort 1 and Cohort 3, there was a cohort with the potential use of the TAR-200 as a key tool for chemoablation. Look, the TAR-200 activity in intermediate risk NMIBC. So the Cohort 3, nearly 90% of the patients achieve complete response. So totally another population of the refractory patient, but the use of these drugs could be very wide in different objectives and different settings, but it is opening a wide range of possibilities.


The two take-home messages that I would like to send are the overall use of erdafitinib in the refractory patient and the concept of chemoablation, which has been already published in the literature, but which was I would say expanded in terms of discussion after this ESMO 2023 in Madrid, and I think it's very interesting for us as urologists to take that into account. Thank you very much.


Ashish Kamat: Thank you so much, Professor Rouprêt. I mean you summarized a lot of data in a few slides in a short time, so thank you for doing that. When you think about the different options that we have for our patients, what do you think is the future as far as intravesical versus systemic? You talked about the toxicity, right? What about convenience for the patient and efficacy? So where do you see the field moving? Do you think we're going to go completely away from intravesical or is intravesical here to stay?


Morgan Rouprêt: No, I think intravesical is, I would say there is a natural cavity. It's very logical to treat there. This is where we do the surgery. So to deliver the drug on site makes a lot of sense. The question is whether or not we need an additional treatment to consider the potential micrometastatic environments. And is the treatment of the tumor within the cavity enough? It is unsolved at the moment, but I do believe that we will need the intravesical option. And when you look back at the mirror with the fast track approval of pembrolizumab as a systemic drug in the refractory patient in the United States, maybe you can confirm what the information that I have, but it was not really a success in terms of volume of prescriptions and so on when it was translated from basic research to daily practice.

So there is also the problem of the adherence, not only for the patient but the physician community. I'm sure that the urologists have been trained and are used to do that, so it's not because they're used to that, we're not going to change the paradigm, then we be open-minded. But at the end of the day, it doesn't seem very logical to treat such a small, tiny localized disease only with systemic treatment.

Ashish Kamat: No, you're right. As far as the approval of pembrolizumab, even though it's approved, a lot of patients, when they hear the side effects, decide not to use it, right? So you're absolutely right, but it's great to have the approval because now we can build on the backbone. That's another question I wanted to ask you because at ESMO it was also presented where they had the intravesical gemcitabine TAR-200 with cetrelimab. Any thoughts about that combination, Morgan?


Morgan Rouprêt: Oh, it makes sense, as I would say we are talking a lot about the pretzel, but we need to bear in mind that it's only a device, and what is important is the type of treatment which is delivered by the tool. So the TAR-200 is a tool, and the gemcitabine remains chemotherapy. So chemotherapy is supposedly efficient on, I would say, tumors but not on CIS. So that is the first, probably, issue, and in terms of I would say restriction of prescription, but the concept is very interesting compared to I would say instillation done through a bladder catheter on a weekly basis.

So this is on the table. Very interesting. And on top of that, you are mentioning something important. There was a systemic treatment as well based on immunotherapy, and I think that both treatments at the same time is an interesting combination. It's not a sequential treatment, it's a combo. It is done in many fields in oncology outside the GU spectrum, and I think it is something that it is, I would say, very convincing on paper. Then we have to look at the data of course, but it makes a lot of sense.

Ashish Kamat: And Morgan, any thoughts about the selective administration of FGFR inhibitors, for example, because there you need tissue, you have to send it out, either tissue or urine, and get back the results of molecular screening. Do you think that's something that can be easily translated into clinical practice? What is your view on that?

Morgan Rouprêt: It's going to be difficult. It's true that usually when you have the approval of a drug, it has something, at least for us in France, that has to be widely available for everybody. But when you start the discussion around targeted therapy, it means that you need to have access to the molecular platform, and it's only the beginning.

We see that in prostate cancer with the PARP inhibitor, we see that in bladder cancer now with FGFR. So we will expand, I would say, outside the cost of the drug by itself, the cost of the disease management. Maybe for the best because it's also costly for a patient to face a dead-end situation and to come back and forth to instillations that are not working, but I'm not so sure that it is going to be widely available for the world population. So we have to solve that. And at the moment, it's only a discussion that we have between top experts in the field. But when we will need to translate that into practice, there is probably a huge gap in the reorganization that we need to consider for the healthcare system.

Ashish Kamat: So Morgan, again, I always want to thank you for always taking the time to spend with us. I don't want to take too much of your time, but in closing, if you could tell us your top two thoughts or takeaways from ESMO when it comes to bladder cancer.

Morgan Rouprêt: The first takeaway is that non-muscle-invasive bladder cancer has been considered seriously for the first time at ESMO, and this is something that is very important because ESMO has nothing to do with just two cancers, it is all the cancers, and it's very rare to have communication. So NMIBC is coming in the field of oncology, and on top of that, targeted therapy is a possibility. So systemic, intravesical, we'll see, but it is a possibility and a serious possibility with first data that are really convincing. So two messages, very important, not only for the medical oncologists, but for the urologists. So let's follow up on that.

Ashish Kamat: Great. Always a pleasure chatting with you, Morgan.

Morgan Rouprêt: Thank you.

Ashish Kamat: Thank you so much.