Morgan Rouprêt: Thank you.
Ashish Kamat: And with that, take it away.
Morgan Rouprêt: Thanks a lot, Ashish, for your very kind introduction, it's true that it was an honor from the French Republic, but going back to bladder cancer, what is really interesting is that the field is moving extremely rapidly. And the question which was raised by this trial is the same, which was raised by a POTOMAC or ALBAN or CREST test is whether or not we should add the systemic treatment to NMIBC, high-risk naive from BCG, which means the next big field is here because we are not in the refractory setting anymore. We are with all these patients that we are seeing in our daily practice, and it was an academic-driven trial. It is, and I will kill the suspense, it is a negative trial, but I will explain you what is probably important and what are the take-home messages that we have for this debate together with CREST and POTOMAC. So the vast majority of the cases we are seeing, I believe in the Western world, through France, too in the United States is not metastatic or the carcinoma, it's non-muscle-invasive cancer.
And we have a lot of high-risk patient, which are at a risk of recurrence, at risk of progression. And of course, we need to adapt the endpoints when it comes to this step of the natural history of the disease. So usually when you are in a plenary session at the ESMO or the ASCO, you will discuss overall survival. We will be discussing today EFS, which is event-free survival. But the definition we have used in ALBAN was a bit different from the one which was used in POTOMAC and in CREST. And I think it's important to mention that and to underline this fact. We have recruited more than 500 patients all over France and also in Belgium and in Spain, they were randomized to BCG after TURBT, either first look TURBT, or second look when we had T1. So we are strictly respecting the guidelines, and it was one year of BCG only, which makes probably a point that is to be discussed. And BCG plus atezolizumab for the experimental arm. And you see that the primary endpoint was EFS. The definition of EFS is important because anytime you see a recurrence within the bladder as a urologist, you will do a TURBT. So the consequence for the patient is TURBT anyway.
In POTOMAC and in CREST, it was only high-grade events that were considered as a statistical point that needed to be registered, which makes something different because EFS is a TURBT. So when you look at the age, when you look at the sex ratio, when you look at the performance status, there is no surprise. And there was a homogeneous, I would say, repetition of the existence of CIS, as you can see within the experimental arm and the regular arm. When this slide is particularly important because one of the take-home message is that in 2025, BCG remains the key treatment and as an adjuvant treatment, and you can see the duration treatment for BCG and the number of instillation was a bit low, maybe 11 as a mean number of instillation in BCG plus atezo versus 12. So there is no big difference between the two arms. But on the long run, when you make a comparison to POTOMAC and to CREST, it will be something different. The number of cycles of atezolizumab, you need to bear in mind that when we build this protocol, the existence and the experience we had with the atezolizumab within the metastatic field, so we had to struggle to define something which could be acceptable for the population and the patients, because if you propose them more than one year of treatment, it could be a question. So you don't have to be a statistician to understand that the curves are more or less similar.
There is no difference. The other ratio, as you can see, it's close to one. So no differences in terms of event-free survival event. When you look at the forest plot, of course it's a negative trial, but look at the trend when it comes to CIS, you can see that there is something slightly in favor of the use of the system treatment in the CIS population, of course, in a negative trial. But this is why also when we will discuss all the trials together, I was discussing recently with some pulse and we are seeing that we are going through a forest plot nightmare with these three trials because there is a trend in favor of the CIS in the negative trial, a accruing against CIS in the positive trial. So at the end of the day, it's difficult to select the patient that are likely to benefit from the systemic treatment. When it comes to secondary endpoints such as in intention-to-treat populations such as high-grade RFS, you can see that once again, the other ratio is close to one, so no meaningful statistical difference between the two curves. And for overall survival, I will not spend too much time on it because the data are far from being mature. There were only very few events, but it is ultimately something that it is important to recruit when you close the trial.
When you had systemic treatment, you expect the benefits, but on top of that, you are sure that you will face some, I would say, dark-side collateral damages. So there were some severe side effects outside the toxicity of BCG itself that was related to the immune treatment. And you can see that the proportion of immune-related adverse events were quite high. So this is something that we have discussed with the IDMC at several times during the recruitment and the enrollment in the trial. And this is probably a concern from the urologist that are considering the possibility to deliver this kind of treatment. When you look into details, there was no, I would say the existence of BCG plus atezolizumab was not expanding the toxicity of BCG or reversely, there was no surprise in the toxicity we obtained from atezolizumab. There were some, I would say side effects that you can overcome quite easily when you're a medical oncologist and you are used to that. Some other, I would say, side effects were more complicated to overcome and you need to have a seasoned team of medical oncologists. So as a conclusion, the addition of atezolizumab plus one year of BCG had no significant improvement when it comes to EFS. The trial also has to be considered as a negative trial. We all know that there was a positive press release for IMvigor011 saying that the ctDNA should be able to select the patient that are going to benefit from the use of atezo in another stage of the disease.
The question is the use of biomarker-driven patient selection in that population also. We have also to trigger the data around atezolizumab, durvalumab and sasanlimab because three different drugs, there could be differences, but there are other [inaudible 00:08:19] in trials such as the quality of the TURBT, the use of the blue light, the number of T1 [inaudible 00:08:30], the strain of the BCG. So outside the field of medical oncology itself, I think there are several patients and we have opened the Pandora's box with this kind of huge cohort. So it was a French GETUG concept trial. And I want to display on this slide, last slide, the curves of the three trials to put them in perspective. Of course, we have no head-to-head comparison between, but the design is more or less the same except from POTOMAC, which has one year of systemic treatment with two years of BCG and CREST is two years of systemic treatment. So the lowest and the shorter treatment was in ALBAN, one-year BCG appears not to be enough in my mind. Ashish, if you want to discuss, I'm open to listen to any question you would like to raise.
Ashish Kamat: Thank you so much, Morgan, for that presentation and also for putting up this graph here, which I think is a perfect way for us to talk about a few things. It's commendable, first of all, that this trial did read out. But as you and I have discussed over the years, I think all these trials were powered for BCG response in the olden era, expecting BCG to not do as well as was seen in all these clinical studies. So one of the things I've heard you say at public forum, which I completely agree with, is that this really reiterates that BCG is the original immunotherapy, and we as urologists really need to refine how our patients get BCG and recognize that maintenance is extremely important. Any thoughts or comments about that?
Morgan Rouprêt: No, I think that we have been going through BCG shortage in Europe. You are facing more or less the same kind of situation in the US or difficulties, I would say. The strain that you are using now in the US, if I'm correct, is different from the one we have in Europe. We use the Medac. I think you are using the TICE at the moment. In France, the French authorities are struggling to have another, I would say, kind of BCG strain available on the market just to be sure that we will not face any shortage anymore. It's difficult because there is a lot in the pipeline, intravesical drugs, systemic drugs, but so far everyone is coming as a cherry on the cake on top of BCG, as an addition to BCG, but no one is facing BCG and replacing BCG. So it is astonishing to see so expensive new drug and no drug is able to challenge the BCG in its gold standard role.
Ashish Kamat: Yeah. And again, even if you're sitting with patients in front of us and we're talking about the hazard ratio with durva or with sasanlimab being 0.68, the ultimate discussion we have to have with the patient is that the absolute benefit is 5% or 7%, but the toxicity increases about 25% to 30%. So as you mentioned, again, in your talk, we need to be able to select the right patient to be able to get combination therapy. And even in a trial such as ALBAN, which was negative, I'm sure that there will be certain biomarkers, we may just not know it yet, that allow us to select the patients that will benefit. One of them is potentially AI-based pathology and machine learning. And I know that you and I, again, have talked about this, so hopefully we'll have some data that allows us to select patients better. But till then, Morgan, if you have a patient that's sitting in front of you today and says, "Dr. Rouprêt, tell me what I should do. I have non-muscle-invasive bladder cancer. Should I get BCG? Should I get BCG plus something?" How will you counsel the patient?
Morgan Rouprêt: No, to be very pragmatic from the experience we had, because we did a lot of patients in Paris and we had also some centers who were enrolling patients in the other trials. I will not go into that direction at the moment, so there is no clearance for the European market for sure, but let's imagine that we have everything between our hands regardless of the decision of the market. It would be difficult for me knowing what is going on in the field to advocate the necessity of a systemic treatment. I would say probably yes to a patient trying to push the boundaries and the limit of the willingness not to undergo a cystectomy and to try to get a benefit. But there would be a difficulty on a one-to-one situation on a personalized medicine pathway to let him know according to the characteristic of his tumor, CIS, multifocality, and so on, how it could be the good person responding to the treatment. So honestly, it would be a discussion, one-to-one discussion, and yes, I could consider to give it in certain situations, but not to a broad population of patient.
Ashish Kamat: Yeah, and I think data from KEYNOTE-676, which allows patients to initially get induction, and then if they have a recurrence, to come in with IO pembrolizumab, might be a good way to reserve the toxicity for patients that truly need it. Morgan, you have received a high honor recently. So deviating from bladder cancer, share with our audience the honor that you received.
Morgan Rouprêt: Yeah, thanks a lot. So it is nice for me to ask me about that. So the French Republic was based after the French Revolution, and then one of the first French regulator of this republic was Napoleon Bonaparte, and he created an award which is the Legion of Honour. So it's a very famous award in France, which has been existed since Napoleon was in charge of France and partly of Europe. And so it is reserved to civilian and military people who are dedicated a lot of time. So obviously for me in the field of medicine and that are struggling to defend the image of France within the world. So I was really honored to get this award from the French president. So I carry it on my jacket, as you can see. And when you look at the French president anywhere in the world, he is always carrying the same kind of sign, which is the fact that he belongs to the Legion of Honour. So thank you so much for emphasizing this very French award and this very recent ceremony that I had. Thank you.
Ashish Kamat: Of course. Congratulations once again, and thank you for taking the time.
Morgan Rouprêt: Thank you. Thank you so much. Thank you. Thank you so much.