Paolo Gontero: Thank you very much.
Ashish Kamat: So Paolo, we've had you here multiple times. We've had you online several times, and of course, we've talked about a lot of things in bladder cancer. Today, let me pick your brains a little bit on this whole notion of BCG-naive disease and BCG-unresponsive disease, because we're seeing now in the BCG-naive space, we have BCG plus IO, which is intensification of therapy. We have about a 7% benefit for patients, some toxicity. On the other hand, we have people saying, "Well, we don't need to intensify treatment because we have treatment if the patient becomes BCG-unresponsive." So how are you thinking about this whole treatment paradigm today?
Paolo Gontero: Well, I think that there are several ways to look at this topic, certainly in the European perspective where at the moment really we lack a number of, let's say, bladder sparing options that are effective. I think it would make absolutely sense to try to intensify the let's say, so called BCG-naive population. By the way, BCG-naive is a term that may no longer be used in the future, because nowadays, we take for granted that BCG is definitely the only standard of care for higher risk non-muscle-invasive bladder cancer.
Ashish Kamat: So let me have you pause there. That's provocative and I'm glad you brought that up. So what are you thinking? You're thinking that the BRIDGE study will show that gem/doce is better than BCG and it'll be used more often. Tell me why you said that.
Paolo Gontero: Certainly, I'm very much curious to know about the result of the BRIDGE trials. Gem/doce is working very well in the BCG-unresponsive, so why not should be really, really very effective in the BCG-naive setting? The other thing is that the EAU classification picked up these subgroup of very high-risk non-muscle-invasive bladder cancer, which actually are still nowadays consider as having radical cystectomy as a primary option. And we know that patient don't want any longer to have a radical cystectomy. The guidelines have mitigated a little bit this dogma by saying that BCG for three years is an acceptable alternative options, but certainly we know that particularly the T1 very high risk multifocal is a disease with a very high risk of progression. And then it comes, of course, the concept of intensification. What is really leaving me a little bit, let's say, confused is that we always based our concept of trying to reduce the risk of progression and we are still going into the BCG to really try to prove this concept that BCG affects progression.
Now we have these trials, combination trials that really address an important endpoint, which means you reduce the risk of high-grade recurrence, which is okay because having an high grade recurrence means that you are leading or heading to being unresponsive and the prognosis is very bad. We know about 30 or more risk of progression at five years of BCG response, but at the same time we'll not be able to see an impact on progression. And so that's the reason why these figures makes the whole story a little bit confused. And you mentioned the fact of toxicity. Toxicity of systemic immunotherapy is something that in many European countries, the urologists are not going to handle. This toxicity is anyway not negligible, I would say. We're talking about 20% immune-related toxicity. So I think it's really something that we have to balance. But as I said, at the same time, the very high risk subgroups really needs an alternative because if we want to be more relaxed towards our patient, we need to be able to tell to our patient that we are doing something more than just giving BCG.
Ashish Kamat: So when a patient comes to you today, Paolo, let's assume it's a young patient in their early 50s and they have this very high risk category of non-muscle-invasive bladder cancer and they ask you, "Professor Gontero, I know you're recommending radical cystectomy to me, but I don't want a radical cystectomy." What is the next best thing? For that patient, are you going to discuss IO with BCG or are you going to just do BCG and then try something if they have a recurrence?
Paolo Gontero: This is a good point because at the moment in Europe we don't have the combination approved and at the same time what we can give as a potential [inaudible 00:05:45] option that is really shown efficacy in a BCG-responsive setting is the combination of gem/doce. So we are really, really, very much received. All other alternative options, trying single agent intracycle chemotherapy, device-assisted chemotherapy is really, really something that has a very, very blurred efficacy profile. And that's the reason why we are really, really, let's say, we have a problem. We have a real problem, but definitely if I have to decide today this patient who are discussing the MDT is probably the type of patient that will try to intensify.
Ashish Kamat: And then let me ask you, are you using anything other than grade stage and histology to help identify which patients you think would do well with BCG and may not do well with BCG? Because I know there are many markers being developed, there's AI based markers, there are others, but most people that I talk to, and including myself, we don't use those markers. I'm curious in Italy, in Europe, as your experience with the guidelines, what's the thought process behind using some of these immunohistochemistry markers, AI-based markers?
Paolo Gontero: Well, let's say that at the moment we do not have any marker that is validated with a prognostic effect. We know that since many, many years ago the UroVysion marker was assessed several studies and one of these studies was conducted by yourself, and the predictive utility was quite interesting. The question is, once we have a marker that tells you that after a single, let's say at the end of the induction course of BCG, you have a 60% chance of having a recurrence again, then what would you do? Or would having this anticipatory answer affect what you're going to do later? Because in the end nowadays, we are coming to the discussion that patients, and I hope it will happen also in Europe with more options being available, we'll end up having multiple bladder sparing treatment just sequenced.
And so the question is, is it really so relevant to have an anticipatory effect and then maybe switch to another treatment when you are actually not 100% certain that you will have the recurrence. But that's just a kind of speculation because I agree that moving towards having predictive of a markers, predictive response that are very, very highly sensitive, I think it's certainly a good way to use this marker, but I think it's in very, very selective populations like the very high-risk BCG-naive or even more in BCG-unresponsive.
Ashish Kamat: Yeah, I think I agree with you because if you just have a marker that tells you a little bit of separation of the curves, how do you counsel the patient? But if you already have one of those very, very high risk patients that you think really needs a cystectomy and then you try BCG and then you get a marker such as UroVysion and it looks like the patient's not going to respond, then at least you have some more reason to maybe counsel the patient to either switch treatment or do something. But I think it has to be very personalized. So Paolo, you've obviously been to many EAUs, many AUAs. Let me ask you here at this AUA, what are you looking forward to the most?
Paolo Gontero: This is a very good answer, but certainly what I really like of the format of AUA is the practice-changing paradigm. And what I'm really, really happy is that in the last few years there's been a lot of these new practice changes in bladder cancer, whether it's non-muscle-invasive or muscle-invasive. So really the field has really just shown a dramatic shift and hopefully we are going to sooner or later render what was considered the best characterization of a surgeon, which is radical cystectomy, maybe an obsolete procedure or a procedure that we are actually going to use in a totally different setting you doing today.
Ashish Kamat: Well said. Thank you for taking the time.
Paolo Gontero: Thank you very much.