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Gautam Jayram: Coming off the heels of a very successful Bladder and Kidney Cancer Academy a few weeks ago in Philadelphia, we've had a lot of movement in community urology to really improve how we're managing and handling these diseases, really minimizing gaps in care that a lot of us have inherited from various limitations in infrastructure and some of our practice environments. So I have picked the five things that I think stick out to me. If you don't like them, too bad.

So, intermediate-risk disease—it kind of occupies this very vanilla space in bladder cancer. A lot of movement, a lot of activities in high-risk disease, BCG-unresponsive disease, and then moving towards advanced therapies in advanced disease states. But intermediate-risk disease is arguably one of the more common disease states that we see in the community. We have plenty of patients who have low-grade disease; they come back.

We manage them in a bunch of conservative ways. However, there is an explosion now of intravesical and novel therapies that are trying to come earlier into this space for a multitude of reasons. And so we have to look a little bit more deeply into this type of disease to understand: Should we be treating this differently? Should we intensify our approach? The guidelines suggest that in intermediate-risk disease, we should consider perioperative chemotherapy. We should consider administration of a six-week course of induction chemotherapy. Maintenance can be considered for a year, and really, office management fulgurations of patients with established disease—I would argue bullet points one and four are the bullet points that we probably do the most of in the community. Not many of us are doing six-week induction intravesical chemotherapy, and not many of us are doing maintenance treatments because of the perception that this disease is relatively benign.

IBCG and other groups have now published some data that helps us understand this group of patients better. Not all intermediate-risk group patients are the same. I tell bladder cancer patients—sorry, I tell bladder cancer patients there's two things: we're always looking at recurrence and progression. Recurrence is generally a nuisance; progression means danger. And so what we're trying to understand is, are there things in these groups of patients that can help us predict those elements? And of course, there are: tumor size, multifocality, recurrence patterns, and previously failing intravesical therapy. What's really important to know is that you can counsel these patients, and you can prepare for these patients differently based on these risk factors—something we really don't think about. We have risk factors for a lot of other cancer states, but we don't really put intermediate-risk or low-grade bladder cancer patients in this bucket.

But what we can see is that patients who have high risk factor prevalence in this state have a significantly higher chance of recurring and actually have about a 10% chance of progression to invasive disease or high-grade disease. And arguably, that's the group of patients that needs to be intensified. So all of this movement with intermediate-risk disease—a lot of clinical trials are now occupying this space. We're likely going to see an approval of UGN-102 within the next 12 months in this space. Begs the question, how do we do this? What do we need to look for? So risk factors are definitely needed to intensify treatment. The risk factors we talked about should help us say, well, this group of patients should be treated more aggressively, and this group of patients maybe does not need to be treated at all. Genomics is a really exciting part of this whole situation.

If you follow the story here, FGFR tends to be predominant in low-grade disease—60% of tissue, the most recent data is a little bit higher, up to 80% of patients with low-grade disease harbor an FGFR alteration. Now, as you know, we have targeted therapies towards those alterations, which is very exciting. Urine testing is lagging a little bit behind in predicting some of these alterations, but obviously that's going to become a big part of the picture if we can do non-invasive genomic testing on these tumors. Newer agents will carry better efficacy than our current options. The MitoGel concept is basically increasing contact time, and as we know, we have other agents in this space where you're not voiding necessarily the agent out; you're increasing exposure to the drug, and so those drugs will be better. I think one of the fundamental concepts in this space is, as urologists in our specialty, we significantly underestimate the morbidity of transurethral resection of the bladder, especially in an older and comorbid population.

So there is the opportunity for these therapies to reduce the need for TURBT, which again, I think would be a huge victory for our patients even if we could just space out the intervals. A lot of this is going to also boil down to cost. We are taking a generally meaningless and benign disease—although I told you that there are some risk factors that can predict that that's not the case—and we are now going to apply a significant cost burden to it. So a lot of these things are going to need to be looked at pretty closely.

Moving on, BCG-unresponsive disease. January 2020—this was our only option for BCG-unresponsive disease. Now here we are about five years later. Four common things that we are—the three are FDA-approved, and then Gem/Doce. All of these we've talked about at a lot of our academies and a lot of our meetings. Gem/Doce is probably the academic favorite due to institutional use and some of the data that's been derived at academic centers. However, the long dwell times—there are some patient issues with being irritated, unable to be easily given in independent centers. The utilization of Gem/Doce in community urology has not been very high.

However, it's very important to understand if you are trying to become a Bladder Cancer Center of Excellence or trying to do this well, you do need to understand that this is a great option for patients. It's a different mechanism of action; it's not immunotherapy, and so you should try to make inroads towards getting this done. Several groups have worked with oncology sites or oncology centers. We work with the hospital nearby to get this done, and it is an extremely important therapy. Nadofaragene, intravesical gene therapy—the first FDA-approved intravesical BCG-unresponsive option—really favorable dosing schedule every three months.

Patients like that; it's de-intensification from what they're used to, as most of these patients have been heavily pretreated with BCG. And then some buy-and-bill concerns have, I think, recently been ameliorated—J-code and the ASP has been established. It is a buy-and-bill that is going to need some planning, pre-authorization, all of that stuff. But this is something that a lot of our groups are using and feeling pretty comfortable with. Pembrolizumab was approved in January of 2020. Obviously, we know the story here—poor utilization in urology, multifactorial, most likely due to a side effect profile that's difficult to manage. But also, the efficacy is not very good as monotherapy—less than 20% CR at one year. Looks like the impact of immunotherapy is going to be most pronounced in combination therapy, and we're going to see more data coming in the next year. N-803 is the most recent drug in this space.

This was approved about six months ago. This is intravesical immunotherapy; it's an IL-15 agonist that stimulates the immune system and stimulates natural killer cells. Interestingly, it really carries the effect of BCG that's co-administered with BCG, but you see significant improvement when they're administered together. It is a six-week induction with maintenance. It's a very new drug; the buy-and-bill is still being established, but we expect this to be a very interesting drug for our patients. So you know how I put all this together now is—a radical cystectomy is obviously still an option, but the goal is to push off cystectomy as much as possible. As someone who does a lot of cystectomies, I can say that my use of cystectomy for BCG-unresponsive disease has gone down dramatically over the last five years. And I think that's the goal: preserve the bladder, give patients options, and as more therapies come into the mix, we can sequence, and we can continue to hope that patients stay free of progression.

A patient-centric approach is now possible. A lot of these treatments, as we talked about, vary in their administration and their quality-of-life impact. The clinical trial story here, as someone who's heavily involved in this space, it gets a little bit murky and complicated. There is so much activity in the space that's exciting, but I think we all have to understand what the big picture is. We're all going to hear about CR rates, and we're all going to hear about durability. But the problem is, what's going to drive the show in community urology is access, logistics, and really the practical matters of delivering bladder cancer care. So I'm not one that really focuses on CR rates. As we talked about, a lot of these trials are run very differently. Some trials utilize re-induction, anytime CR, mandatory biopsy at 12 months—that muddies the water for all of these CR rates, and you just can't compare across the board.

I think we have a lot of good options, but really what's going to carry utilization is going to be how easy is it for you in your situation to give this drug. I put this in because I think it's important: BCG-unresponsive does not mean BCG cannot work. Ashish Kamat's group, I think, put out a really cool small retrospective study, but 75% of patients who met the criteria for BCG-unresponsive disease can have a complete response with another course of BCG. So again, I am a BCG defender. It is cheap; it is great; it works well. Yes, there are patients who do not respond to BCG completely, but if someone comes to your office and says, "BCG won't work for this," you can tell them, "You are wrong." BCG is still something that can work in this group of patients and will, I think, be part of the overall sequencing post-BCG-unresponsive categorization.

And then again, financial toxicity to our patients needs to be discussed. All of these drugs are going to significantly change our bladder cancer patients' kind of state access. All the drugs we have right now are fairly cheap, and we don't really think about it, but this is going to be a big part of the picture. Moving on, one quick slide on muscle-invasive disease and advanced disease. Niagara was really the biggest abstract that came out this year in muscle-invasive disease. This is basically adding durvalumab, which is immunotherapy, to GemCis prior to radical cystectomy. Huge trial—1,000 patients—very well done in Europe. Tom Powles and his group did a great job with this trial. And they showed that the addition of durvalumab to GemCis improved all outcomes, including path CR and overall survival, which is something we have not seen in this space before compared to GemCis alone.

So possibly practice-changing. I think it's really going to impact the community medical oncologists that we work with because most of these doctors are not giving dose-dense MVAC, so they're going to toss on durvalumab to GemCis, and then we're going to be doing radical. So the systemic situation in advanced and perioperative disease is changing as a lot of chemotherapy is no longer the cornerstone for advanced disease. We're using EV and Pembro—or the medical oncologists are using it—and so a lot of things happening, but immunotherapy continues to be really embedded now into everything we do in bladder cancer. And then ctDNA—this is, I think, really interesting and exciting. I call it the ultra-sensitive PSA for bladder cancer. Now we are starting to see a lot of interesting data. The graph you see on the bottom right is from the IMvigor study, which was a negative adjuvant trial of Atezo versus placebo post-cystectomy.

And the reason this study is actually still even being discussed is because the subgroup analysis that looked at ctDNA positivity versus negativity—you can see in patients that are ctDNA positive, two things stand out. You can select patients for whom to give adjuvant treatment to, number one. But number two—wow, those curves are really different in terms of recurrence and survival over the next five years. So it's an incredibly powerful prognostic tool, and now there's a lot of applications for utilizing ctDNA. I can tell you in my practice, if patients have had neoadjuvant chemotherapy and they have a negative cystoscopy, a negative CT scan, and negative ctDNA, I do not take their bladders out. I put them on observation. Discuss as you will—it's somewhat controversial, but I truly believe that that's going to be the future. Moving on to kidney cancer, there's two quick things.

Adjuvant immunotherapy in renal cell carcinoma—this was approved two years ago. Prior to 2021, we only had a tyrosine kinase inhibitor in this space, but there was no overall survival benefit that was ever seen. Pembro was then approved for this group of high-risk "patients," which we'll talk about is a little bit nebulous. Three other trials, though, in the 18 months after approval were released, and none of them showed a difference in disease-free survival. So there was a little bit of a question of, well, is this a false signal, or is this something that we should really be considering? Well, this year, the Toni Choueiri study read out even further, and there was now an overall survival benefit associated with patients who got pembrolizumab post-radical nephrectomy for high-risk tumors, which again, we have never seen in this space before and is actually quite difficult to show in an adjuvant setting within a short period of time.

So this, I think, has validated the fact that for our high-risk renal cell carcinoma patients post-radical nephrectomy, pembrolizumab is the standard of care. Now, it doesn't work for everybody; it shouldn't be given to everybody. The label is T3, node-positive, or T2, any Grade 4 sarcomatoid. What I would tell you is, as we know as urologists, not all T3s are the same. You could have a little bit of T3 with sinus fat invasion versus a big renal vein tumor, that T3b. So I tend to treat these patients aggressively with immunotherapy if they have vascular invasion, T3b disease. And patients, as I think we've talked about at several meetings, tolerate this very well, and I think they get a benefit. Last slide that I have is RCC-specific PET imaging. So a lot of us—our practices have been changed by PSMA PET. It has really improved, obviously, primary staging, how we approach recurrence, and how we can target recurrence.

The same thing is now happening in renal cell carcinoma. Carbonic anhydrase IX is a novel target that is a transmembrane glycoprotein that's involved in the VHL pathway, which, as we know, is very, very intimately linked with clear cell renal cell carcinoma. About 95% of clear cells express CA9, which is kind of paralleling the PSMA story, as we know about 95% of prostate cancers express PSMA. What's also interesting is that CA9 is not expressed in normal kidney. The false positives—and we'll see this trial in a second—the false positives in the trial were all kidney cancer, but they were non-clear cells. So you can actually make the argument that if it lights up on this scan, it is kidney cancer, and there's a 95% chance it's clear cell. So ZIRCON was the study that was recently published in Lancet. This is a big trial—international trial, 300 patients—where they got your classic image-and-resect trial.

They imaged them with a PET if they had an indeterminate renal mass seven centimeters or less, and then they removed it, and the histology served as the reference standard. Just for a frame of reference, cross-sectional CT, which all of us use for this, has a sensitivity of about 70% and a specificity of about 50% for clear cell renal cell carcinoma. CA9 PET now has numbers that are much better than that—86% sensitivity, 87% specificity. Subgroups that were studied in this really reiterate the fact that this is reproducible even in small tumors. So tumors less than four centimeters, which is your T1a group, which is the most common group of patients that we struggle with in terms of how do we manage these patients. And then even in a group of patients under two centimeters, you had very similar results in terms of sensitivity and specificity.

Then lastly, extrarenal lesions were detected more frequently when compared to CT alone. So this is going to probably start serving as a primary staging modality in high-risk renal cell carcinoma patients, which is going to be terrific because one of the big problems that we have in this space is understaging—not understanding patients' metastatic burden before we do a radical nephrectomy. So in my opinion, the implications of this are that we're going to have superior disease staging and the potential for distant staging; you're going to have improved triage capability for patients in whom biopsy is not easy, right? We all have a group of patients who can't come off blood thinners, biopsy—they don't want an invasive procedure. And remember that 86%, 87% sensitivity and specificity—that actually approaches the numbers that you have or that you see for a renal mass biopsy. So this is really a very cool non-invasive type of biopsy that I think is going to dramatically help our ability to stage and treat patients.

And then the last bullet point—this is kind of a wave in the future—but a lot of excitement about radioligand therapy in prostate cancer. We're seeing a lot of our groups are bringing in PET scanners and operationalizing PET because, again, it's such an important part of how we treat prostate cancer. The opportunity for theranostics in kidney cancer is here, right? If 100% of these that light up are actually kidney cancer, you're going to start seeing radioligand therapy be close on the horizon for renal cell carcinoma. So before I close, Jason and Gordon were kind enough to let me include just a few slides from the Bladder and Kidney Cancer Academy, which were survey slides, but I think represents a lot of how far we've come in community urology over the last 10 years. Just simple survey things, but I think a lot of it's food for thought, surveying over 100 participants.

Do you have a cystectomy expert in your practice? Eighty to ninety percent of groups said yes. The vast majority of groups—big groups—are doing their own cystectomies and complex surgery. Do you run clinical trials for kidney and bladder cancer in your practice? Again, really, really cool. Now, the trial landscape in bladder, kidney, and prostate cancer is really starting to change, as many of our groups are very active. Almost every big group has some clinical trial presence. Do you have a multidisciplinary tumor board in your practice setting? This is something that I laugh because this is my initial metric question to ask somebody if they say, "Well, how do we start building a good program?" Just get a couple of people together who are interested in this stuff and have a weekly tumor board. It's very simple; it's something that's underutilized but really can improve outcomes. And most groups are doing this.

Do you utilize navigators for kidney and bladder cancer treatment or surveillance? A lot of our groups now are incorporating—and we have seen this in prostate—but a lot of our groups are incorporating the same personnel to identify patients who are BCG-unresponsive, patients who are high-risk renal cell after nephrectomy, and those groups of patients are being directed towards champions. Interestingly, and we mentioned this, are you giving pembrolizumab in your site for kidney or bladder cancer in your practice? About 60% of respondents say yes. This is obviously a skewed group because they came to the meeting, but this still represents, I think, a lot of progress. Some of the other survey data I've seen is that about 30% of large groups are giving immunotherapy in their own practice. And I think that as things go forward and this disease—these drugs continue to move into earlier states—that's going to be very important.

Are you giving newer intravesical agents in your practice? You can see Anktiva, Adstiladrin, Gem/Doce. Now, a lot of our groups are starting to operationalize how to give some of these bigger and newer drugs. And then, are you utilizing enhanced cystoscopy, which is in the NCCN guidelines in some setting? Remember, this is a difficult tool to get in the office, but it is a quality metric for how we're doing with our bladder cancer patients, and I would say a high percentage of patients have access. So overall, I think we're making a lot of progress in the community in terms of improving outcomes for both bladder and kidney cancer. That's all I have.