Petros Grivas: Ashish, first of all, thank you for having me. It's always a great pleasure to see you and of course talk to you. I learned a lot from you every time we speak. And we synergize analyzing data through the international bladder cancer group that you are leading, other meetings that we get together and ask you to use one of those meetings. And I'm very excited about it. I think the progress that has been made in the field is tremendous over the last several years. And I go back to ESMO 2025, Ashish. And every single presidential symposium, Saturday, Sunday and Monday had a bladder cancer trial, urothelial cancer trial presented. So it's tremendous. This is the impact and the positive benefit for patient care and outcomes. So in ASCO GU, as you said, many datasets will be there. It's a lot of work by many people around the world. I think many colleagues are interested in seeing the data from EV-304 or KEYNOTE-B15 trial. Just to remind the audience, this is a trial that is evaluating perioperatively enfortumab vedotin, anti-nectin-4 antibody-drug conjugate, plus pembrolizumab anti-PD-1 combination compared to neoadjuvant gemcitabine cisplatin, gem-cis chemotherapy. And I say perioperatively the pembro because it's a neoadjuvant component.
I think four cycles of pembro neoadjuvantly. And if I remember correctly, there are five combination cycles adjuvantly and then remaining a few cycles of pembro alone. So it's a sandwich approach as compared to neoadjuvant gem-cis, four cycles from neoadjuvant gem-cis with no built-in adjuvant therapy based on the timing that the trial was designed. We saw a press release, and this is for cisplatin-eligible patients, of course. There was a press release that you, me and others have seen looking at the key result that this was a positive trial, meaning perioperative pembro EV prolonged overall survival and event-free survival and resulted in a higher pathologic complete response rate with a neoadjuvant component compared to gem-cis. So everybody is excited to see the data. And of course how this can impact practice. We already know from EV-303, KEYNOTE-905 trial in cisplatin-ineligible patients that EV pembro prolonged event-free overall survival compared to no perioperative therapy in cisplatin-ineligible patients. So I think everybody's looking forward to that trial. What do you think Ashish? I know from the urologist that point, it's also highly relevant.
Ashish Kamat: Yeah, no, thanks for sharing that, Petros. And I really think absolutely everybody's really going to be waiting for those results. Because we saw the 303 data, the cisplatin-ineligible. Of course, we saw the NIAGARA data. But I think what happens now is so long as access is not an issue, let's assume we live in Disneyland and we have access to everything. If access is not an issue, it makes it really easy for us on the urology side to be able to counsel our patients on neoadjuvant therapy. If you don't have to worry about the hydronephrosis, we don't have to worry about the platinum eligibility. And I think that's what's going to be key from across the board. So really looking forward to, I think Matt Galsky is going to be presenting that data and that abstract. So we're really looking forward to that. If I have to put you on the spot, Petros, and put your thinking cap, prediction cap on, we saw the excellent results when it comes to PathCR in patients who are cis-ineligible. Do you think that the cis-eligible patients will have a better PathCR, similar PathCR? What do you think the implications are for bladder preservation?
Petros Grivas: That's a great question. And it's hard, of course, to predict to your point. But the way I think about it is what factors may impact PathCR. One thing that comes to mind is the initial clinical T-stage that both you and me know it's hard to know exactly whether this clinical T-stage is accurate or not because of the challenge we have in conventional staging. But if we look at the EV-303 or 905 cisplatin-ineligible patients from ESMO 2025, that trial, a significant proportion of patients, I think 75 or 80% had clinical T3 or T4, or I think there were very few patients with N1, if I remember. And that population was a higher-risk population. So I think the composition of clinical T2 estimated versus higher clinical states may impact the PathCR prediction. Of course, other factors that are not easily measurable and confounding is the extent of TURBTs, or we saw about 9%, single digits, less than 3% of patients in KEYNOTE-905 had a PathCR based on TURBT alone. So a small proportion may get that, especially if it's a smaller tumor with more radical TURBT, if I can use that term.
And also the other thing is the number of cycles. In EV-303 trial, we had three cycles of neoadjuvant EV pembro. Here in EV-304, we have four cycles. So whether that may impact PathCR is hard to tell. I think the other detail is that you may have talked about is if we look at the PathCR strict definition takes a ypT0-1N0 in patients, of course, who got cystectomy, but the denominator in the intent-to-treat population may take all comers. So if you take patients who did not have radical cystectomy for whatever reason, patient choice and beyond, that denominator will be larger, so the actual fraction will be lower. So the PathCR will be lower in the intent-to-treat population. Because it includes those who did not have surgery versus the subset of patients who had radical cystectomy. So in the KEYNOTE-905 EV-303, we saw a 57% PathCR in the intent-to-treat. But it was slightly higher between 60 and 65% or so in those with cystectomy. So I think we're going to end up in a similar range, but again, we have to see the data.
Ashish Kamat: Yeah, no, absolutely. Shifting gears a little bit, another topic that you and I have talked about, which I think is going to be featured fairly extensively at ASCO GU is ctDNA. Because Tom Powell is going to, again, talk about the ctDNA-guided adjuvant atezolizumab, IMvigor011, and then Pooja Ghatalia is going to talk about the RETAIN study and how ctDNA might guide us in bladder preservation and adaptation in the RETAIN study. What is your prediction as to how people will see ctDNA in bladder cancer when they leave San Francisco at the end of this month?
Petros Grivas: It's another great question, Ashish. And it's hard to predict the future, of course. But my thinking is right now, where do we start with ctDNA? We have very robust data from IMvigor011 in the context of prior trials. IMvigor010, CheckMate-274, TOMBOLA trial from our friend in Denmark. I think all this data set so far tell us a couple of things. Number one, ctDNA is highly prognostic. It can be very strong in terms of the prognostication of recurrence and survival. ctDNA-negative status undetectable is a good thing, much lower chance of progression and death. ctDNA positivity is a very negative prognostic factor. That's a prognostic question. The predictive question is what we saw from IMvigor011 and a few other trials that in immunotherapy-naive patients, when you had radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy, in those patients when you're about to decide about adjuvant nivolumab that has been approved by FDA and EMA a few years ago, in particular scenarios based on high risk of recurrence, if you're in that scenario and you are discussing the benefit-risk, there was benefit in that trial clearly in the ctDNA-positive patients post-cystectomy, and that's event-free survival.
So event-free survival benefit in the ctDNA-positive subset. So if it's event-free survival, I can argue that subset of patients with high risk for recurrence who are contemplating adjuvant nivolumab, and they have positive ctDNA, likely benefit from that option. So it's a tool. ctDNA is not perfect. We have to understand as a field what the false positive means, how do we interpret that? At the same time, we do not recommend doing ctDNA serially every two months or three months. It's not there yet. We have to get the data from different trials. Because my worry is we cannot extrapolate from one trial to the other, or one setting to the other. We have to look at the data in the context that were generated. So the RETAIN-2 trial, for example, by Dr. Ghatalia, folks say it's great effort, dose-dense MVAC plus nivolumab, I think it was the treatment neoadjuvantally, and there was an option for bladder preservation. Very interesting to see the data there. Because as you and me have worked with Andrea Necchi and others, how to define clinical complete response in those who get induction or neoadjuvant systemic therapy, if they have negative cross-sectional imaging, negative cystoscopy, negative mapping biopsies, negative urine cytology, conventional definition of clinical complete response, can ctDNA in the plasma and/or urine potentially add or not in that definition? Can this increase a level of confidence that these patients will do well over time?
I think it will be critical to ctDNA data in that context and see how patients do with or without cystectomy in that setting. And I think the more we test the DNA across different trials, the more we can get those answers.
Ashish Kamat: Yeah, no, well said. And I really think that this appropriate definition is something that many have proposed. We propose, you've been part of course, the effort that we've had jointly between the San Raffaele Group, Global Society, IBCG, but hats off to the Europeans who are actually doing a prospective study in a basket type to actually first prove if the CCR matters, and if the definition matters, then to go on to successive outcomes. And Alexandra Masson-Lecomte is really leading the effort there. So I think that's great. Petros, so much to talk about, if you look at the list of the late-breaking abstracts, the oral presentations, the actual trials in progress, it just goes on and on and on. And I'm pretty sure UroToday is going to have their writers and people updating everybody, so that'd be great. Obviously, looking forward to seeing everybody there. Lastly, before I close, I want to pick your brain on a topic in the non-muscle-invasive space. And not to put you on the spot because this is systemic therapy, but I'm sure you saw the release by Pfizer announcing that they're not pursuing sasanlimab, at least currently, for a BLA filing despite the positive results from the CREST study. So BCG plus IO, two positive studies, one negative study. Everyone was looking forward to the BLA for approval for the subcutaneous formulation. There's obviously going to be expanded data presented at GU ASCO. What's your sense as to going into GU ASCO, the debate between BCG plus IO versus BCG done appropriately? What's your sense? Again, not to put you on the spot, but I'm sure you can tell us something.
Petros Grivas: It's a great question. I know you, me and many others have been discussing this in various meetings. And it's an interesting one because if you look at the CREST trial and the POTOMAC trial as well, the CREST trial tested sasanlimab subcutaneous for two years, I think. And POTOMAC durvalumab intravenously for one year as an addition to intravesical BCG induction maintenance. By the way, both of those trials saw how important maintenance is of BCG intravesically, which I think is relevant discussion in the context of the BCG shortage that we're still experiencing. But BCG matters and maintenance matters. But the question is, do you add value by adding the systemic checkpoint inhibition? If you take CREST and POTOMAC, there were positive trials. ALBAN, on the contrary, was a negative trial testing atezolizumab. There were differences in those trials. Just briefly, some thoughts more than me, but the sample size of ALBAN was smaller, was a smaller trial. There was some differences in whether induction was allowed in, I think, CREST and POTOMAC and may not have been allowed in ALBAN. And also how you measure the grade of recurrence and ALBAN counted everything as a recurrence while CREST and POTOMAC focused on high-grade recurrence. This may be, and of course PD-L1, PD-1, and all this discussion stays current, but this may be some of the reasons why ALBAN was negative in terms of the prominent point.
But if we look at CREST and POTOMAC, they were both positive in a pre-agreed primary endpoint. So someone can say a positive trial should be an option for the patients. At the same time, I think people recognize that systemically administered checkpoint inhibitors can have side effects, and can have immune-related adverse events. And if you look at the data is about 20% or so, more or less, in terms of treatment-related adverse events that can be clinically significant and sometimes severe. And a few of them, a small proportion can be life-changing. A small proportion of that, 20% like hypothyroidism or adenosine deficiency or things like that. Overall, I think it's a value-based proposition. And if you ask different people in the room, you get different answers. If you ask patients, even patients may have different approach. How much they value the benefit in terms of event-free survival, which is reduction the risk mainly driven by high-grade recurrences, non-muscle-invasive recurrences in the bladder. That is what's driving these endpoints. There were very few patients with muscle-invasive disease or metastatic disease, not powered to answer that progression question. So it's driven mainly by high-grade non-muscle-invasive recurrences.
This is important, of course, but how do you balance that with the risk of systemic toxicity. And also the therapy burden for those patients being treated for up to a year or up to two years? Of course, the logistical factors, do we have our colleagues in urology managing those patients? Do we have the resources to do that? Do we have the time, advanced-practice providers, nursing team, do we have the space in clinic to do this? Do we have infusion room to do this? There are many logistical factors come to play. So I don't have a yes or no answer for you. I think it's individualized patient by patient and maybe driven by the risk of recurrence. Maybe I'm hypothesizing patients with very high risk from the diagnosis, maybe those with high-risk T1 plus CIS plus LVI, maybe some component of variant histology that you may talk about radical cystectomy as a potential upfront option. This may be patients who might be considered for systemic checkpoint inhibition. I think one size does not fit all, but it's a case-by-case discussion.
Ashish Kamat: Yeah, absolutely. So Petros, I think even though you covered both sides of the debate that's going to happen at GU ASCO on this topic really well, I still want to encourage everybody that's listening, please show up for the debate. Because I'm sure it's going to be a phenomenal point-counterpoint.
Petros Grivas: Ashish, one more quick thing I want to share with you, we actually have a poster. I want to let the team and the people know Jeannie Hoffman-Censits, who is at Johns Hopkins. She's the chair. I'm the co-chair of a phase-two/-three trial for upper tract urothelial carcinoma, localized upper tract. And we're presenting data for the cisplatin-ineligible cohorts, single-arm phase-two with gemcitabine plus durvalumab, gem-durva combination in cisplatin-ineligible patients with localized upper tract as neoadjuvant therapy prior to radical nephroureterectomy and lymph node dissection. Jeannie will present the poster. So I want to make sure I share with you and the community.
Ashish Kamat: Absolutely. Looking forward to it. We could talk about ASCO GU and what's going to happen there forever, but I think this was a great way to get you to highlight what you think are some of the important things. Really looking forward to seeing all our friends and colleagues at ASCO GU, all the patients, and of course the UroToday folks. Looking forward to seeing what they have to show us. Thanks, Petros.
Petros Grivas: Thank you so much.