Bogdana Schmidt: Thank you so much for having me.
Fernando Maluf: Hi, Ashish. Hi, Bogdana.
Ashish Kamat: So, we had a really great session in London at EAU26, and one of the topics that we talked about, and you guys debated, is something that's a hot topic across the globe right now, because patients are getting a new standard of care in many places. Neoadjuvant EV pembrolizumab is hitting the path CR rates out of the park. We've had NIAGARA, we've, of course, had refinement in standard dose and sandbag, all of this happening over the years. And what's happening now is people and patients are talking about, do we need to have the bladder taken out? Can I just get a surgical or preplanned treatment and then avoid a bladder removal? And of course, you guys were tasked with taking both sides of the coin. And Bogdana, you were tasked with saying it's a risky business. So tell us why you think it's a risky business.
Bogdana Schmidt: Thank you so much for giving me the chance to talk about this. Well, important thing to know is this is a very exciting time for this space. The fact that we're even having this conversation is fantastic. Bladder preservation is something that we've always been hoping to offer to our patients, and the patients are really interested in this. The idea is attractive. You think that with maximal effective systemic therapy with EV pembrolizumab being that treatment regimen that we're all discussing now, you want to be able to push forward and see if we can preserve the bladders at this time. But there are a lot of questions we still can't answer. We don't know who the best patients are for bladder preservation. We don't know which characteristics really define a complete responder after neoadjuvant therapy. What does that clinical complete response mean? How do we measure that? Is that MRI? Is that CT? Is it cystoscopic biopsy? Is it urinary tumor DNA, circulating tumor DNA? How are we going to define that entity? What surveillance strategy are we going to use to monitor? Is it going to be Q3-month cystoscopy, three-month CT scans? For how many years? That's a lot of follow-up for these patients if they do as well as we want them to do.
And again, how long do we monitor them? And frankly, what do we mean by bladder preservation? And again, as you frame this conversation, we're talking about leaving the bladder intact, not radiating the bladder, not offering an additional treatment to it, but rather just surveilling the bladder in that sense. So, long-term data that we have is actually pretty old. It's from a very old series from Memorial Sloan Kettering, started in 1994 that looked at folks who got best systemic therapy at that time, cisplatin chemotherapy, for solitary selected tumors, got a maximal TURBT, and were followed. And again, all of these patients achieved a clinical complete response as that was defined, so no visible tumor on biopsy or imaging. After neoadjuvant chemotherapy, they had over 10 years of follow-up in this series. And what they found is overall, patients actually did better than you would expect. Forty-one percent were alive with an intact bladder, but 38% recurred in the bladder, nine of which were muscle-invasive. Eleven percent of those patients ended up getting a cystectomy. And among the patients who relapsed in the bladder, the five and 15-year mortality rates were pretty significant. That was old standard chemotherapy. Now, let's talk about a more updated experience looking at the RETAIN trials. So this was, again, selected patients with specific mutations, had an accelerated MVAC regimen in the RETAIN-1 trials looking at metastasis-free survival two years for the whole cohort. In the active surveillance group, two-year metastasis-free survival was 72.9%, active surveillance group, 76%. Primary endpoint of that trial was missed because 68% of active surveillance patients recurred, and only less than half kept an intact bladder without metastasis. So RETAIN-2 went a little step further, and these are the patients they had in their active surveillance cohort, 22 patients. If you look at what happened with them, 14 of them were recurrence-free.
Four had a non-muscle-invasive recurrence. One patient had a pelvic nodal recurrence, and three had a muscle-invasive recurrence. And if you look at that, certainly those patients did better than the RETAIN-1 cohort. Sixty-eight percent of them were metastasis-free with an intact non-irradiated bladder, but that's still over 30% of patients whom this didn't work for. So we're figuring out who the better patients are, but I'm not sure we're seeing that this is safe to skip surgery. And again, looking at SURE-02, small single-center trial, looking at pembrolizumab with sacituzumab govitecan and cisplatin ineligible or refusing patients. Short follow-up, only about 14 months. Clinical complete response, about 39%. So interesting, but six patients had distant metastasis, very short follow-up, and clinical complete response under 40%, that means most patients still need more. So this is provocative, but not enough to make this the standard of care. So you mentioned enfortumab vedotin, pembrolizumab regimen earlier. Of course, we're all excited about a 57% path CR. We want to be able to use this, but that path CR data was established with cystectomy still performed in a timely window. Path CR at surgery doesn't automatically validate our clinical complete response endpoint, which we haven't yet defined because clinical complete response is not the same thing as durable control. And while ctDNA can help figure out metastatic risk, not useful for local bladder recurrences. And if we look back at RETAIN, of the 21 local recurrences, only two were ctDNA positive and all the patients who developed metastasis had a local recurrence that preceded it.
So a negative ctDNA test can't substitute, at least for now, for a bladder-directed assessment, we need a urinary marker. If you miss that window, you could lose the opportunity to cure the patient. Until we figure out who the best patients are, how we're going to define complete response, we don't have a way to surveil these patients. We don't have a mechanism for how long we're going to do it, and we don't really know how well they're going to do in the salvage setting. So while promising and exciting, and I want us to be talking about this in a few years, I don't think we're there yet now. For now, still risky business.
Ashish Kamat: Thank you so much, Bogdana. You presented that aspect of things really well. Again, we do have to exercise some caution, and you highlighted those points well. Now, I'd love to hear from Dr. Maluf. Why do you think we're ready?
Fernando Maluf: Okay. So first of all, I thank very much Ashish for the invitation. It's a real pleasure to discuss this topic with Bogdana. So my test today is to show why this is a smart, driven strategy. So first of all, I'd like to thank Ashish and Bogdana for the opportunity to discuss this important topic, the bladder preservation in cCR patients, a smart data-driven strategy. So the pCR rates in muscle-invasive disease with the modern era trials and modern results. So these are the pCR rates with the modern trials using immunotherapy plus chemotherapy such as the NIAGARA trial and also the antibody-drug conjugate with immunotherapy. So we can see that the response rates, the path CR with chemotherapy is about 33% and goes up to 42% in NIAGARA trial and to almost 60% in both EV303, EV304 trial. So really it's almost double the pCR rate with these modern agents. For the patients who had a pCR with a modern agent such as the NIAGARA trial, the event-free survival rate is above 92%. So clearly there is a benefit in achieving a pCR rate, which again is a biomarker for not only bladder preservation, but cure. So how can we improve this strategy aside from pathology imaging using more sophisticated tests?
So this is Matt Galsky trial published in Nature in patients with mostly invasive disease treated with cisplatin, gemcitabine, nivolumab for four cycles. And for those who achieve CR by cystoscopy biopsies, urine cytology and MRI, they undergo no cystectomy followed by nivolumab for eight cycles. And the primary endpoint was two-year MFS and less than PT1 and zero disease. Out of the 32 patients, 31 achieved a complete clinical response, and the MFS for those patients were excellent. Seven out of eight patients had surgery done in this complete clinical CR. And of those seven patients, they had T2 or less disease. During the follow-up, two other patients developed no invasive disease, and two other patients developed metastatic disease. But if you look at the overall survival at MFS, they're basically excellent with this strategy of no local treatment in patients achieving a cCR. Because of the high predictive value of a clinical CR, the mutation analysis did not add value in this trial. On the other hand, we can look at the modern era, not only molecular tests, but also imaging tests with MRI. And those patients who achieved a complete or almost complete response by MRI, they had also an excellent MFS that we can see in the curves. So now how can we build up aside from, again, the pathology, the imaging, and the mutation analysis? And that's the role of ctDNA. So here are an example of two trials evaluating ctDNA in muscle-invasive disease patients treated with neoadjuvant chemotherapy or neoadjuvant ICI prior to cystectomy.
We can see that ctDNA is a strong prognostic factor as a baseline pre-cystectomy and post-cystectomy. And this is the RETAIN trial. This trial evaluated cisplatin-based therapy with nivolumab for three cycles. And in patients who had a clinical complete response, they find no disease by TURBT CT scan urine cytology, plus a mutation positive score by NGS, they were advised to go active surveillance. For the other group of patients with a non-clinical or pathologic response by TURBT, or the absence of mutation positive analysis, they would undergo local treatment. And of the 22 patients on active surveillance, again, with clinical complete response plus a mutation positive analysis, more than two thirds remain with the bladder intact and metastasis-free. In this trial, the RETAIN-02 trial, ctDNA was associated with metastatic control, but not local control. So the question is, if ctDNA is such a powerful tool of predicting metastatic control, how we can predict the presence of still tumor in the bladder, particularly superficial tumor, and that's the role of utDNA. So this is the databank of NIAGARA trial, which was presented at ASCO GU. And in this presentation, we show that we can see that utDNA was associated with a higher frequency of superficial disease after neoadjuvant chemotherapy plus durvalumab. On the other hand, ctDNA positive was associated with muscle-invasive disease and/or nodal disease or metastatic disease. So basically, there is a synergy between utDNA for superficial disease and ctDNA for more advanced local disease or extravesical disease.
And of course, there are many trials and many definitions, and that's one of the papers that was just published that was led by Andrea Necchi and Ashish Kamat of the new endpoints with these next-generation bladder-sparing perioperative trials. So in my personal view, in the very near future, with all this data of ctDNA, utDNA, pathology, molecular analysis, yes, we are heading towards a more safe, secure bladder preservation strategies. So this is an example of a trial that is about to start in the next two or three months that Ashish Kamat is part of our steering committee, evaluating patients with muscle-invasive disease. It's a Brazilian trial randomized before starting neoadjuvant chemotherapy and durvalumab between radical cystectomy or TURBT followed by chemo radiation, where both arms receive adjuvant durvalumab. So this trial, again, is using modern perioperative regimens and is the first randomized trial looking for bladder preservation comparing cystectomy versus radiochemotherapy.
This trial, again, is a Brazilian trial involving more than 25 public hospitals in the country, and we are going to evaluate ctDNA and utDNA as baseline pre-cystectomy and after cystectomy in the patients. And also there is another trial that is going to compare in patients who have a complete clinical response using TURBT, urine cytology imaging, ctDNA and utDNA, and randomize those patients between radical cystectomy, followed by no local treatment, looking for bladder-intacted cancer-free long-term survival, local recurrence metastatic disease. So in conclusion, there was an improvement in path CR rates with the new regimens, almost doubling the response with chemotherapy. There is an improvement on molecular image test assays. There's an integration of imaging studies, pathology, mutation analysis, ctDNA and utDNA. So we are reaching extremely high rate of predicting a real PCR and precisely select patients for bladder preservation, if not now, in the very, very near future. Thank you very much.
Ashish Kamat: Okay. That was a great presentation, Fernando. And again, both of you did such an outstanding job in London itself that I feel like it's great to hear this for a second time. So again, both of you presented the data. Both of you talked about how we are at a point where we have to study this. And even though you were assigned with the task of defending it, Fernando, it's not like you're saying we should just jump into it without keeping our eyes wide open. And I think that's what Bogdana was saying as well. So let me ask you both a couple questions. Today in clinic, and let me start with you, Fernando, when you see a patient that you have started on pre-cystectomy therapy and the patient now sits in front of you and says, "Dr. Maluf, on the imaging, I have no tumor, there's nothing in my bladder. Why should I have my bladder taken out?" What do you tell that patient today?
Fernando Maluf: Well, first of all, I don't think that is fully established that radical cystectomy is better than chemoradiation. And that's the reason of the REDEMPTED trial that you are part on because we know that radical cystectomy has mortality, of course, depending on the rates of how experienced the service and the surgeon is, aside from all comorbidities. So the first thing, we don't know what's the better local treatment. So many times, not with me, but of course with you and Bogdana, patients with a clinical CR by imaging, TURBT and adding ctDNA, or utDNA, patients are asking us, "Do I need to take the bladder out?" And I'm not sure. And there are two things that I think is important to point out. One is having no local treatment at all. And I think we're reaching to this point, but are not yet at this point. However, if the patient doesn't have CIS or multiple bladder tumors, it's a focal tumor that had a complete response, I think it's very reasonable to radiate this bladder without taking out. Again, in patients with incredible response, focal disease and no criteria, again, for diffuse disease or a bladder that is not functioning very well. So yes, I think we do have patients that decline surgery and if these patients fall in this category, feel absolutely comfortable to offer radiation therapy as a local treatment, which is less morbid than radical cystectomy.
Ashish Kamat: And I'm glad you're studying that, Fernando, because again, if a patient asks me today, what is the treatment paradigm that has shown a clear improvement in survival, it is the package deal. It's either NIAGARA protocol with surgery and then the adjuvant phase or EV303, 304 with surgery and the adjuvant phase. So as of today, at least, we can't tell the patient that we can skip one or selected components of this. But yes, studying that like you're doing in REDEMPTED is really a good thing. Bogdana, what's your take on how you counsel patients today? If they're starting on a journey, they come to see you, they have muscle-invasive disease, are you offering them neoadjuvant therapy as a way to spare the bladder, or are you offering it to them as part of a package deal to improve overall survival and event-free survival?
Bogdana Schmidt: Yeah, I think of it the way that you do. I'd love to pick and choose the parts of the regimens that have shown to be most effective that I like the most or that patients would like the most. But if you want the statistics that these regimens allow for us to present to our patients, you've got to do it as the package. I tell patients that we are at the best place in bladder cancer that we've ever been as far as our ability to offer patients treatments for metastatic disease, for locally advanced disease, and for non-invasive disease. And wherever they're walking into today is a much better situation than it was two years ago, five years ago, and certainly tens of years ago. And I want them to take that for the win that it is. If the situation changes and we have more data from trials like Fernando's REDEMPTED trial, from the BRIGHT trial, looking at radiation and immunotherapy in that post-neoadjuvant chemo setting for other trials that I'm sure are coming like the RETAIN trial, looking at keeping the bladders in, once we have the data that we can present numbers to those patients, I'd love to be able to offer that. But as of right now, I think it feels like a gamble. I have things that I know work with this success rate. I don't feel comfortable not offering that to the patients today.
Ashish Kamat: And let me be a little provocative here and say, of course, when we're talking about bladder preservation, ideally it would be the patient's intact bladder that has not been radiated either because radiation has its downsides. So the ideal situation, Fernando, for me as a surgeon would be not to have to take out any bladders unless I have to, but then offer some additional therapy. And whether it's intravesical or systemic, what's your sense? And let me start with you, Bogdana. What's your sense in patients who have a really good response? It's going to be to continue on with systemic therapy? Is it going to be intravesical? How are we going to think about this in trial design?
Bogdana Schmidt: Yeah, I agree. I think the best combinations are going to use the best parts of what we have. A good intravesical agent, may be something with an advanced delivery system, a chemo agent that we're familiar with, coupled with a neoadjuvant chemo immunotherapy combination with some amount of treatment offered to the patient post in that sandwich model where you get that neoadjuvant bit coupled with something in the bladder and probably for longer than we think... I mean, I assume that they're going to need therapy for six months to a year for us to feel comfortable that this is real, and then you stop, and then you surveil and you see if it comes back. And then what do you put back on? Well, it depends on where the recurrence is. Is it local? Then maybe you just treat the local. The reality is that we're grasping at pieces of evidence that don't quite exist. We all know patients who started in the metastatic setting on the original EV trials who had metastatic bladder cancer with an 11% CR, none of those patients got cystectomies or many of them didn't. So those patients exist that were metastatic that had a complete response with bladder intact. I have one of those patients in my clinic, I marvel at him every time I see him, but I can't tell everyone else that this is going to be their outcome.
Ashish Kamat: And Fernando, I mean, when you're seeing patients with systemic disease that have a dramatic response systemically and are now free of their cancer, but are developing bladder recurrences, how are you thinking of that primary versus systemic and bladder preservation? What's your thought process there?
Fernando Maluf: If you're looking at the NIAGARA and the two EV trials, I mean, half of the patients globally we achieve a path CR, which means that the other patients who do not achieve, they're going for some kind of local treatment such as surgery or radiation. But just look at these patients with the path CR. The chances during follow-up of having metastatic disease are very low. However, I think it's important, despite what the local treatment is, to maintain the adjuvant part that you're going to discuss offering the IBCG meeting in August. So I think the systemic part is important. The other important part for those patients who have a local recurrence or another primary tumor, which again, it's very common in patients who have the bladder in, like 30% who have a second primary during the follow-up. For these patients, if the superficial disease, you treat a superficial disease, and if it's muscle-invasive and you follow the patient closely, I think this few number of patients, it's very rare to lose the timing, again, to save the patients with a local procedure such as surgery.
So at the end of the day, in my opinion, taking the bladder out in patients with a path CR are going to benefit very little patients. Why? Because some will develop systemic recurrence, very few despite the bladder. The other group will develop superficial disease that are going to be treated with intravesical treatments, and some of them will have a great response. And for those who don't, they can be salvaged by cystectomy. And for this tiny group of patients with muscle-invasive disease, they can be salvaged as well if they're going to be followed closely. So at the end of the day, I don't think... Again, the data is not full of papers, it's not 100% solid, but I think we are not benefiting many of the patients taking the bladder out, in my personal opinion, with, again, aggregating all these biomarkers together. But agree with Bogdana. I mean, more trials should be done, but at the end of the day, I think we are going to reach this conclusion.
Ashish Kamat: Great points from both of you. And that's why both of you are such an integral part of the effort that we're going to have here in Houston through the IBCG 2026. So looking forward to that. Always a pleasure to have you. Thank you for taking the time. Stay safe.
Bogdana Schmidt: Thank you.
Fernando Maluf: Thank you.