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Ashish Kamat: Hello, everybody. And welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat. And it's a pleasure to be joined today by Professor Shilpa Gupta and Felix Guerrero-Ramos. Welcome, both of you, to the forum.

Shilpa Gupta: Thank you.

Felix Guerrero-Ramos: Thank you very much.

Ashish Kamat: So we're following up on the debate that you had at the rapid fire debate session. And we have an excellent write-up that was done by the UroToday team that folks can reference, and we'll put the link at the bottom. So today, let's keep this at a discussion level. So let's say hypothetically, Shilpa, or in the real world, we have a patient that comes to your office, has not seen a urologist yet because he or she is referred directly to you. Healthy 60-year-old. Really no comorbidities. Let's keep this simple. Has what looks like to you a high-grade T2 bladder cancer and, say, N1, N2 disease, not biopsy proven. How are you counseling this patient on what to expect next?

Shilpa Gupta: So Ashish, by definition, this is a patient with locally advanced urothelial cancer. And for such a patient, depending on where in the world we are, there are excellent systemic therapies. Now, if I were to see this patient in my clinic today, I would say this patient needs systemic therapy with enfortumab vedotin and pembrolizumab. That is the level one evidence for the standard of care.

Other reasonable options are, if the patient is eligible to receive cisplatin, gemcitabine, cisplatin, and nivolumab based on the CheckMate 901 data. And in many parts of the world where EV and pembro are not available, just doing platinums followed by avelumab maintenance if the patient were not to progress is also very reasonable, also based on level one evidence.

Ashish Kamat: So Felix, Shilpa has not mentioned anywhere in her discussion with the patient that she would refer the patient to a urologist. And I'll bring her back to that question. But if the patient sees you first, how are you counseling this patient? What to expect as part of the journey?

Felix Guerrero-Ramos: Well, the first thing here is, especially for the audience to be aware of, these patients are the ones who most benefit from a multidisciplinary approach. So these patients should be individualized. Any of these patients should be individualized and commented in the MDT meetings. In my opinion, these patients—there is a mistaken statement on these patients. Some people say these patients need neoadjuvant chemotherapy or neoadjuvant treatment plus radical cystectomy.

I do not think so. I agree, like Shilpa says, this is a locally advanced disease with the need of a systemic therapy. And radical cystectomy will be offered to some of these patients on an individualized approach. For example, if the patient has a good clinical response after EV pembro and there is a resolution of the node-positive disease and we can see there is a complete response in the disease which is outside the bladder, I would consider a radical cystectomy as a consolidation for this patient.

Ashish Kamat: Great. And Shilpa, I didn't mean to imply that you don't consider MDT because I know you're a strong champion of that. I was just making a little joke. So let's assume this patient now sees you and is in a place where they don't have EV pembro. So you're forced to use GC plus or minus durvalumab or whatever you want to use. But you're using GC-based therapy. This patient is able to tolerate a good five to six cycles.

And now, Shilpa, you're seeing a complete resolution radiologically. Like none of the nodes are biopsied because they looked like metastatic disease to the nodes. But now there's a CR in the lymph nodes. What are you now thinking about in that patient? The bladder also looks clear. It was a good TURBT, and the bladder looks clear. And now the nodes have almost resolved or you have a radiologic CR. What's the next steps for your patient?

Shilpa Gupta: Yeah. So this is great news that the patient responded so beautifully, Ashish. And based on the data from level one evidence, patients who have a CR to this therapy should continue the maintenance avelumab if this patient got just GC. And I want to highlight what Felix said. If patients have a complete resolution of lymph nodes outside of the bladder, they can think about consolidation.

But I want to point out to the audience that all the data for the consolidated surgeries, a lot came from MD Anderson, MSK, those were back in the 1990s when we did not have anything other than chemotherapy. We did not have immunotherapy. There was no effective systemic therapy, and all we had was surgery. So in my mind, for this patient to undergo a surgery may be a moot point because the patient has already achieved the best response and now we can maintain it with immunotherapy.

Ashish Kamat: So yes. You referenced our data, and it used to be when we didn't have any good maintenance therapy that we would offer patients with N1, N2, N3, even all the way up to the renal vessels, a full RPLND because the only ones that actually seemed to have survival benefit were those that had consolidation, including with surgery. That being said, though, Felix, today in your practice, when you see a patient and you're talking to them about continuous maintenance IO therapy, what percentage of patients are willing to undergo ad nauseam IO therapy with the potential side effects? And what number of patients, when you counsel and say, well, let's consider local consolidation, say, well, tell me more about it?

Felix Guerrero-Ramos: Well, I think there are two populations here. One population is that metastatic population, those patients with metastases that even with a complete radiological response, I would be more willing to offer a maintenance avelumab rather than radical cystectomy. But for those patients who have locally advanced disease, like the case we are seeing, N1, N2, if there is a complete response, in our MDT, we are more eager to offer radical cystectomy to these patients.

Of course, the rationale for this is for those patients with only node-positive disease, we tell them that we believe there is a clear chance of getting cured of their cancer after the radical cystectomy, rather than with more systemic therapy because even the patients with just node-positive disease in the clinical trials are not a big proportion of the patients.

And if we offer a patient—when there is a metastatic disease, I mean M1a or M1b, we offer these patients usually consolidation with immune checkpoint inhibitors. And some of these patients, we are learning new things every day on these patients. After a certain time or after toxicity that prevents them from having more IO, they might be subjected to a radical cystectomy if still there is a complete response that we can see is a young patient and we can do some consolidative surgery.

Ashish Kamat: Thank you. Shilpa, you've given several talks on this and you're the expert. So in most of the perioperative studies, N1 patients, and especially N2 patients, are not part of the population. But in NIAGARA and, I believe, in one of the others, there is an N1 population. So based on your read of that subgroup of patients, what's your sense of this whole perioperative paradigm for patients with N1 disease?

Shilpa Gupta: Yeah. So I'll make two points, Ashish. So first of all, these patients, the ones with N2 disease, about 27% were represented in all the frontline metastatic trials, like KEYNOTE 361 and IMvigor130, DANUBE, EV pembro. So this patient by default is belonging to that category where we're doing the frontline metastatic therapy. And to your point about perioperative trials, all the trials exclude even N1 except for NIAGARA. You're right. But the only patients who were included—very carefully selected—total only 10%. So a minority.

And in the ENERGIZE trial, where there's gem-cis nivolumab, we've not seen any data yet. But a very minor subset of patients were allowed if they had N1 less than 10 millimeter size in the short axis—not even 1.5 centimeters. So we have to be very careful that this is not your classic perioperative patient, but really a locally advanced patient.

Ashish Kamat: Now, let me be a little provocative. Because when we're talking about these patients that have locally advanced disease, let's just say it's T2 or T3, even N1—let's ignore the N1 part of it. If there were T2 or T3 and they had perioperative or pre-surgical therapy and they had a complete response in the bladder, we would tell these patients that bladder conservation at this point is still to be studied on a clinical trial even though we have emerging data that it might be safe in a certain population.

But now with this patient having, say, T3 and N1, if they respond completely, now we're telling them that let's not do radical cystectomy. Let's go on a maintenance therapy because of the JAVELIN study. How are you reconciling this? A little bit of a disconnect between what we're telling patients with T3 disease and what we're telling patients with T3N1 disease. And let me throw this to you, Shilpa.

Shilpa Gupta: So I think just T3 disease, all these patients are part of the perioperative paradigm. But if we are removing the node-positive situation from there, then I think consolidative surgery is still the standard of care outside of a clinical trial, where we can hope to preserve bladders by offering them chemoradiation. So I think in that situation, I completely agree. Subjecting them to long-term immunotherapy is not ideal. And we can offer them consolidative therapy. But more and more trials will address this question on a trial basis.

Ashish Kamat: And Felix, your viewpoint.

Felix Guerrero-Ramos: Well, I think we have to differentiate these two populations, node-positive and node-negative patients. We've had these trials, like the RETAIN1 trial preliminary data, and preliminary data from RETAIN2 and the trial. I think in the future we will be performing less radical cystectomies in muscle-invasive bladder cancer. I believe that.

But still, as I showed in the EAU slides, we see that up to 4 to 18% of the patients who preserve their bladder with a complete response can develop metastases in the follow-up or after preserving their bladder. So one important concept here is how we are going to redefine the clinical complete response—not only based on imaging, TURBT, cystoscopy, and cytology—but also using, for sure, ctDNA, utDNA, and maybe some other tools that let us be more confident about the complete response assessment.

Ashish Kamat: Yeah. Great. I was just going to come to that. So now let's assume this particular patient because we see these patients in the clinic. We see these patients. We have to counsel them. Some of them say, well, I would rather go on long-term immunotherapy, but then they get side effects. And then the question becomes, how long is too long?

On the other hand, there are some patients that really are having symptoms from their bladder or the bladder tumor is still present. It's not completely responded. And then you're like, if you need to address the bladder, what do we do with the nodes? But let's keep it simple for the purpose of this discussion. Let's assume the same patient comes to you. Today, Felix, are you using ctDNA to guide your treatment decisions?

Felix Guerrero-Ramos: Not at the moment. We are only using ctDNA in the clinical trial setting. We don't have it as a standard of care.

Ashish Kamat: And Shilpa?

Shilpa Gupta: I'm not using it to guide treatment decisions, Ashish, but we have the privilege to test it on patients. So we are just using it to gather information.

Ashish Kamat: And Shilpa, if you put this patient on maintenance IO therapy—let's assume it's avelumab—how long are you targeting in your mind the duration of therapy for this patient?

Shilpa Gupta: Yeah. So that's a really good question. In the original JAVELIN Bladder 100 trial, there was really no end date to maintenance immunotherapy, just like all other older trials. But we now know that beyond a maximum of two years, really there's no need to continue IO. But in my practice, I really tend to stop it even as close as one year if patients continue to demonstrate that they have a CR. So if you've had two or more scans showing that the patient has no evidence of disease, I talk to them about stopping the immunotherapy. And I think it has worked really well. For patients who are such extreme responders, they've never really had to go back on it.

Ashish Kamat: OK. And Felix, are you considering some patients after they have a good response, for example, and they want to undergo a radical cystectomy? Are you offering radical cystectomy to them right away? Are you saying let's try maintenance IO for a while. And then if you stay clean, then I'm more confident that you've responded, and then I'll do a radical cystectomy. What's your sort of sandwich approach?

Felix Guerrero-Ramos: Well, yesterday I had a little discussion with one of my patients who was referred by the medical oncologist because this was a metastatic M1a patient with lymph nodes up above the aortic bifurcation. And this patient, after over one year of EV pembro, stays and remains in a complete response. We've done PET CT scan. We've done MRI. Normal CT scan, cystoscopy. Cytology is negative. And even this patient—this is in the private practice—so he's been paying for a Signatera testing. And his last ctDNA was in February, which was negative.

So this patient was referred by the medical oncologist because he wants to have a radical cystectomy done, and he wants to be “rescued” with the radical cystectomy. And we are going to discuss this in this week's MDT meeting. And probably, I would feel comfortable offering this patient an upfront radical cystectomy. Regarding those patients with chemotherapy—because I cannot offer, of course, a maintenance IO to these patients with EV pembro—if we are considering a radical cystectomy, I think that the sooner we do it, if we have a complete response, the best for the patient, because there might be some patient with a complete response who will not respond well to IO or whatever. So I think that as soon as you have a complete response, if you are evaluating performing a radical cystectomy, you should do it as soon as possible.

Ashish Kamat: Yeah, I think it's great that we are in these current days when we can have debates like this because not too long ago, we had really nothing to offer patients other than—we used to call it sometimes desperation surgery. But now we have options, and we can tailor it to patients. And this has been a great discussion, but obviously, we have to come to a close. So just closing points. And let me start with you, Felix, and then we'll give the last word to Dr. Gupta. Your main take-home message for patients with N1, N2 bladder cancer coming to the clinic?

Felix Guerrero-Ramos: I think it's exciting times for patients and for us as well. And I think in the near future, some of these patients who usually didn't undergo radical cystectomy will have to be debated in MDT meetings. And many of these patients—we will be performing more cystectomies in locally advanced patients than we did before even having these new agents. But I think we will be able to consolidate and cure some patients, adding surgery to a previous efficacious systemic therapy.

Ashish Kamat: Right. And Shilpa?

Shilpa Gupta: Yeah. So I think what I will say is a little bit different. That in the era of effective novel systemic therapies, once we've achieved an extreme response, a complete response, and utilizing the upcoming biomarkers like ctDNA—if that remains negative—then I really don't see the need to subject these patients to a huge life-altering surgery. And I think no patient is going to want to have it. It's going to be really hard to justify a surgery because I see the data from the olden days—surgery was desperation surgery, like you said, Ashish. But that's not the case anymore. So that's my take-home message.

Ashish Kamat: So again, great discussion. And it's really nice that patients have access to experts like both of you in an MDT setting. Thank you very much for taking the time and spending it with us, and have a great rest of the day.

Shilpa Gupta: Thank you, Ashish.

Felix Guerrero-Ramos: Thank you, both. Bye bye.