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Sam Chang: Hi. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center, and I am always very, very fortunate to have incredible experts in the field looking at different types of urologic cancers, usually focused on urothelial carcinoma. And I can say that we truly have an expert today.

In Nashville, many of our patients want second opinions to different places. And when we talk about MD Anderson for urothelial carcinoma, there's one person I refer them to and it's Dr. Neema Navai who is professor at MD Anderson. He's actually the deputy chair as well for the Department of Urology there. He is the go-to person here from my standpoint. When it comes to excellent clinical care and every patient that comes back after seeing him, is incredibly happy, pleased, and obviously quite fortunate.

So Neema, thank you for spending some time with us. I asked you to talk about a recent Journal of Urology Plus article that you all were looking at—the role of pT0 perhaps as a biomarker, perhaps not a perfect one, but I thought it was quite thought-provoking and wanted to get your take on that. And again, thank you for your time.

Neema Navai: Dr. Chang, it's—

Sam Chang: Sam. That's the kind of respect that Neema has, so please call me Sam, and we look forward to your presentation.

Neema Navai: Sam, it really is a pleasure. It was a very kind introduction, and I hope to live up to it. I will say that the feeling is mutual. I have never heard a cross word about you. In fact, quite the opposite. I think you've got an embarrassment of riches when it comes to advocates out there. Everybody sings your praises for good reason, including your patients.

I'm really excited to share some of my thoughts around node-positive bladder cancer. I think it's a really unique opportunity for us to accelerate the field of biomarker-driven research. So I'm going to share some slides here. This has been a longstanding interest of mine. This actually dates back many years to when we tried to approach SWOG and develop a trial in this space, which we're still continuing to advocate for, because I think it's really a necessary space for urologists in particular to understand when, for example, surgical intervention is appropriate for patients who initially present with node-positive bladder cancer.

I also think it provides us a unique opportunity to learn something and learn something unique. We have long sought for effective biomarkers in this space, things that will bridge the gap between initial disease and potentially bladder-sparing therapies safely. I know there's a couple of trials examining this, notably looking at DDR mutations, but I think that some of that work would be accelerated by looking at a different cohort of patients.

So with that, just for my disclosures, they're presented here for reference. They're not going to impact any of the substance of my talk today. And I'll briefly go through this, so we have time for discussion. I want to touch a little bit on what people view as some of the rationales around nodal metastatic disease. And this really speaks to our underlying assumptions. One is that limited nodal metastatic disease may be cured with surgery, obviously with the addition of chemotherapy in most cases.

Now, that is largely driven by retrospective studies where patients were actually clinically node-negative, and they were found to be pathologically node-positive at the time of surgery. And they do have some evidence of long-term survivals, even in pathologically node-positive disease. But it's unclear in the patients that initially present with node-positive disease whether that bears out. And that's an important feature that we'll come back to in some of the rest of this talk.

Surgery in the setting of clinically node-positive disease really should only be reserved for those who have a clinical complete response. This has been longstanding dogma. It's what we tell many patients, that you need to achieve a robust response before we do consolidative therapy, but it's unclear whether or not adding surgery, for example, in that scenario helps any more than the systemic therapy already did for the patient.

What we see is that the pT stage remains prognostic even in those patients. So there is some other interplay going on, that it's not just the clinical response that informs how patients will do. In those patients with a pathologic CR, they're going to experience the best survival. And I think this is one of these very obvious factors that we all speak to, but it makes all the sense in the world, yet it doesn't tell us very much at the same time.

It's unclear whether adding a radical cystectomy, for example, in that setting benefits the patient beyond what the systemic therapy did in and of itself. And then obviously, consolidating in the setting of residual disease is unlikely to benefit the patients. I think that is again dogma that we all follow—if patients don't have clinical responses, we don't feel that, for example, consolidative surgery makes sense. But it may actually be the inverse of that.

It may be that there are some patients with locoregional disease that is systemic therapy-resistant, which should be exactly the patients that we're consolidating, because systemic therapy has failed and their only option for cure comes from consolidation.

Some of the large studies that have come before that help give us some insights into this space include a seminal study by Dr. Galsky many years ago now in JCO, that showed those patients that had local consolidative therapy, even when they presented with node-positive disease, actually had the best survival, as opposed to those that had no cystectomy included, or a local aggressive therapy included in their treatment paradigm.

This was the first hint. But one of the things that worries me is, in that same article in JCO, there was another study looking at the same database that looked at patients with metastatic disease—this was not just nodal disease; these were patients with extrapelvic nodal disease, bone, and visceral metastatic disease—and those patients that had high-intensity local therapy had a similar survival benefit.

Now, some would interpret that to mean that the survival benefit from the prior study is real, and it is also real in visceral metastatic disease. And I actually think this is what tells us how much bias these retrospective data sets contain, because I don't think there is any biological rationale for a patient with visceral metastatic disease to benefit from local therapy. And that five-month survival difference is about matched to what we saw in the prior Galsky data.

I think that really tells us that it's selection bias, and that's how much selection bias is contained within this. So we went and tried to embark on a set of studies ourselves at MD Anderson to look at whether or not we could refine selection of patients. We looked at clinical response, and we found that, yes, if you have a more robust clinical response, you are likely to survive with additional therapy better than if you don't have a clinical response. But it still doesn't answer the underlying question, which is, does the surgery itself add to that survival?

We looked to see if there was an oligometastatic phenotype—can we identify unique patients that will benefit—and those with less metastatic burden, single metastatic sites, do better than those with multiple? But we wanted to take it a step further and say, you know what, is there an opportunity here to identify a biomarker?

This was really borne out from an assumption that there is too much contamination in the T response in bladder cancer, meaning that the TUR itself may render as many as 15% of patients pT0 at the time of cystectomy, even for advanced disease. And that level of contamination means if our output is the complete response in the bladder, we are unlikely to identify real biomarkers because there's too much contamination from the TUR.

We saw the node-positive patient population as the perfect example of how we might accelerate this, because if they have pN0 response, that was 100% attributable to the systemic therapy—you can't TUR a patient into pN0 status. And so we designed a trial looking at exactly this. And what we found is that those patients that can achieve a complete response, both in the bladder and in the lymph node, clearly did far better than those that could not.

But what is really informative from this trial is that those patients that had a complete response in the node after biopsy-proven node-positive disease prior to systemic therapy had a unique biological signature informing their disease response, different than had we used the pT0 as their response measure for systemic therapy.

And that congruence rate of 13.4% is really what we think is the takeaway and most powerful aspect of this study. I think the opportunity—and hopefully we'll get into this in the questions, and I'll stop with this slide—is how do we actually take this to the next level and design trials that allow us to get to the truly informative biomarker that may allow us to safely, for example, avoid consolidative therapy after systemic therapy in patients. So with that, I appreciate your attention. I'm looking forward to the discussion, Sam.

Sam Chang: Neema, incredibly thought-provoking. So I want to—before we get to look at the pN0 plus-minus pT0, let's start off with the pT0 focus group. Because I think your thought process behind, are we doing too much for people who really don't need it—either they respond to systemic therapy and/or they were actually cured by their initial TUR—is very, very clearly that's the big push that we're having these days by our medical oncologists with the advent of different types of systemic therapies.

So in your evaluation of the pT0, what do you think really—can you a priori determine which of those individuals are which? In other words, was it always a small volume that probably we did that with TUR? It's the ones that had robust elsewhere response that are really pT0 from systemic? How do you think we can better evaluate the clinical T0 that actually corresponds to the pathologic T0?

Neema Navai: It's a great question, and it's one that we grappled with. So there's a study that we were actually the lead group on—I didn't present it today—that looked at whether or not we can trust our assessment of the T response rate after systemic therapy when ascertained clinically, meaning by TUR, and examination under anesthesia, and imaging. And what we found in those patients—so the way the study was designed is patients had an evaluation, and then they all went to cystectomy.

And so the cystectomy pathology was the gold standard. Two-thirds of patients who we did not identify residual disease based on TUR imaging and examination under anesthesia did have meaningful residual disease on their cystectomy pathology. That really was the warning sign for us that unfortunately right now, we don't have perfect measures of residual disease after systemic therapy.

What you might assess as a complete clinical response in the bladder may not be accurate, and it may not be accurate as many as two-thirds of the time. And that's where we feel there's a worrisome factor. You've got to find some other way. Now, maybe there are unique biomarkers, for example, Signatera, that might be helpful in that setting.

But that might also be a longitudinal thing, where it reverts to a negative Signatera, but then it will bounce back. And maybe it isn't helpful when there's very, very low-volume disease, for example, microscopic residual disease.

Sam Chang: To me, that's one of the important questions that, like you said, that we grapple with because just recently—it's amazing to me, some patients, I really never say patients are totally cancer-free in the bladder, even with noninvasive disease, especially T1 noninvasive disease. I think it's a site of lurking, and the question is, do you get localized consolidation with cystectomy or radiation, or do you have to do something? Clearly, you don't have to always.

But boy, that two-thirds mark that you all found—and if you look at the Fox Chase group, one-third, at least, that they thought were clinical T0—it's obviously an area of concern. Let's look at this combination of pT0 and pN0. A lot of work—obviously, the biopsy-proven nodal disease, being able to get that information.

Tell me—I know it's small numbers, but tell me if you were able to tease out clinical indicators of the pN0 that were more likely to respond. Unilateral, small, focal, et cetera. Anything clinically that we could bank on, separate from the genetic evaluation that you found?

Neema Navai: We actually did try to ascertain whether there were clinical features that predicted for pN0 achievement after systemic therapy. And so virtually all the patients that were biopsy-proven node-positive did have systemic therapy before cystectomy. And what we found is that there weren't really reliable clinical factors. So you might imagine that N1 might do better than N2 or N3, that the size of the node—if it's between 1 and 1.5 centimeters—it would be more likely to respond completely than if it was greater than 1.5 centimeters.

And despite our attempts to ascertain something along those lines, we didn't find a clinical factor. We didn't have a lot of these patients that had pelvic MRIs, so it's possible that there are unique imaging characteristics on MRI, for example, that would have predicted or PET-CT scans, where the avidity would have predicted for it. We didn't have enough of that information to do those analyses. So the jury's out a little bit.

But what I think is important to lean back on is if we look at the tail in even metastatic disease for urothelial cancer with systemic therapy, there are not an insignificant number of patients that are cured with systemic therapy that have metastatic disease. And that number ranges—it's maybe as high as one-third of patients actually, in some studies. And that's what we found: one-third of patients that had biopsy-proven node-positive disease had a complete response in the node and had long-term survival as though they had been cured by their systemic therapy.

That tells you something—that even high-burden metastatic disease, there's probably a biological susceptibility in about one-third of patients that renders them cured with systemic therapy alone. The real challenge is, if we knew that, we wouldn't be operating on these patients. If we knew what predicts that, we could apply it to localized disease, and we could save these patients the morbidity of local consolidation. That's really the exciting part, I think, for the future.

Sam Chang: And that tail that you mentioned—that's based on our historical cytotoxic therapies, and now with the ADC combinations, with the—I mean, that tail, obviously everybody's goal is that that tail increases from 15%, 20%, 30% to 40%, 50%, et cetera. And so tell me where you all are going to go next in terms of evaluating, studying, and then helping to determine what do we do with these patients following systemic therapy and responses?

Neema Navai: Obviously, we're excited to try to create the first truly informed bladder-sparing trial in this space. I think that the work that's going on in DDR mutations is very exciting, and we're looking forward to seeing more development in that space. I think leveraging unique systemic biomarkers like ctDNA is also a very exciting space. The advent of additional therapies like enfortumab vedotin plus pembrolizumab (EV pembro) being the most obvious one is a very exciting space.

But how we see leveraging this data moving forward—currently we have an enrolling trial where we're looking at exactly this patient population: patients that have clinically node-positive disease. They're getting systemic therapy in a randomized fashion and then consolidative therapy. And we're using that trial to actually validate biomarkers in this setting. So this is hypothesis-generating. We need to do the more robust studies that actually tell us if we can elucidate a biomarker that can be applied prospectively.

Sam Chang: For those patients, are you getting tissue sampling or something of the nodal disease?

Neema Navai: Yes.

Sam Chang: Oh wow, that's going to be fantastic. It's very, very telling.

Neema Navai: Hard to accrue too. That's a big challenge. And we have thought about expanding that study to include patients that have PET avidity and not necessarily biopsy-proven, but we have actually incorporated in our practice a pretty low threshold for trying to prove nodal disease with a biopsy.

Many times it's feasible, and I do think it helps. If nothing else, it helps tremendously with counseling patients, because in reality, if you know that they're node-positive, it's a very, very different set of conversations that should be had. And so we do a lot of pelvic node biopsies on patients with urothelial cancer. But ultimately, for these studies to be robust, you need to know pathologically what's happening in that lymph node.

If you restrict to patients with only imaging-based node positivity, the problem there is that you get a lot of contamination.

Sam Chang: So let's get even more thought-provoking here while we have just a couple minutes left. We've done, I would not say a haphazard division between localized node-positive, visceral distant mets, but now let's talk about even the worst of the worst patients with visceral disease: lung disease, liver disease, perhaps even bone disease. And we all think we have different levels of, this is not good, this is not good. And each of those that I throw out makes things worse. Any work that you all are doing or thinking about doing for patients truly with worse non-pelvic disease? What are your thoughts regarding next steps, and what are you all studying next as well?

Neema Navai: I think that most of the attention within our framework of trials and studies for patients that have distant or visceral metastatic disease really is on systemic therapy and leaning heavily on sequencing that systemic therapy. So that's where it interfaces with urology. And me as a surgeon, I do think that there is an unmet need. There are some patients—and we're starting to see more of these with more effective therapies, like ADC combination therapies—where patients are surviving much longer than they did when I first started practicing.

And not only are they surviving, which is a wonderful achievement, but they're doing so with the morbidity of their local disease in place. And then the question is, well, can we do something for their local disease to help mitigate some of those issues?

Historically—me personally, but I think also commonly within our field—we've been hesitant to do that because the survival was so poor. The progression rates were so rapid that putting someone through a cystectomy seemed like a road too far to go.

I think that's changing. And so I think the role of quote-unquote "palliative" cystectomy or cytoreductive cystectomy—however you want to phrase it—that's probably a space that people need to start thinking through with the improved survival of systemic therapies, even in patients that initially present with visceral metastatic disease. But I think that jury is still out.

Sam Chang: I agree. And I think that the predictions by some of the people I respect the most in medical oncology regarding "radical cystectomy is dead"—I think it's way, way premature. There will always be, unfortunately, patients with significant symptomatology, et cetera, that can really truly only get relief from cystectomy, be it a palliative, be it a salvage, last-ditch type of effort. But there are always going to be those patients.

But it will be interesting in this day where we have these long-term responses, where we're not so concerned about, hey, if we come off treatment for a period of time, things aren't going to explode. These are all questions that we've all struggled with because, just as you said, do I put the patient through morbidity if they're doing wonderfully at this point? Probably not, no. But for those patients, I think it will be very interesting to see where we go next with the localized therapy.

Neema, thank you so much. Every time I get to spend some time with you, I'm always amazed by your focus, your thoughtfulness, and truly, I was smiling to myself as you were talking about gathering disease from nodal sites or whatever, because I can picture several patients from Nashville when they visit Anderson, within a 48-hour time period. They've obviously seen multiple physicians but have undergone biopsy, cystoscopy, et cetera, imaging.

We have wonderful interventional radiologists, but I think the folks at MD Anderson—there's no question, there are some nodes that I think could be at the top of Mount Everest and they'd be able to sample. There have been some difficult locations that some of our patients have had biopsies on, but I think it's very telling. And so that's why I'm very excited to see your data regarding the response, depending upon what was found in the disease and what was found locally as well. I think it will be very, very telling.

I look forward to seeing you at upcoming meetings and look forward to future publications, and I know we'll be able to have conversations again soon. So thanks again and really appreciate all your efforts.

Neema Navai: Sam, it was an absolute pleasure. I really appreciate the opportunity, and the audience at UroToday—hopefully they'll find this informative. It's great to see you.