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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined by Dr. Ashish Kamat, who is a urologic oncologist at the M.D. Anderson Cancer Center. Ashish, thanks so much for joining us today.

Ashish Kamat: It's a pleasure to be here, Zach, and to talk about this very important topic.

Zachary Klaassen: Absolutely. So this is what was presented at SUO. Great presentation. I'd love for you to go through some of the highlights of your pre`sentation.

Ashish Kamat: Absolutely, just some snippets of the highlights. So I think it's very important for us to always know where we came from. And because of that, I just put forward this whole timeline.

And in short, essentially we have to recognize that BCG has been around forever. But nothing else has really been developed in the non-muscle invasive space other than valrubicin. And kudos to them for actually having a drug, but the disease-free survival was fairly dismal.

So there was a need to educate regulatory bodies. And, of course, there were two groups, the GU ASCO group that Seth Lerner led and the National Bladder Cancer Group that I had the pleasure of leading that sort of proposed these benchmarks to the FDA, which they adopted in 2018.

So it's important for our young fellows and residents to understand that this was essentially a clinical trial definition that we put forward. And this is BCG-unresponsive disease. Essentially, the patient has to have met the definition of adequate BCG, which is at least one attempt at induction and one attempt at maintenance therapy. And if the patient then has either persistent T1 high-grade disease or recurrent T1 disease within six months of the last course of BCG or 12 months of CIS, that's considered BCG-unresponsive disease.

It's, again, very important to emphasize that this is a clinical trial definition, not a clinical definition. We don't want people to assume that this is what they should be following in the clinic. This is mainly to allow us to do single-arm studies.

And of course, when the FDA adopted this and put forward this guidance to the industry, which was very, very commendable on the FDA's part, there was an explosion of drugs. I'm not going to go through the details of pembrolizumab, which was the first to be approved, nadofaragene, which was the second, and, of course, NAI, which is given with BCG. But you can see there that many were approved. And of course, we have TAR-200, cretostimogene, EG-70, which are all currently showing really exciting, promising results which hopefully, we think, will be approved in the next year or two.

This is a nice publication that I sort of borrowed from. And it is actually a figure right from that publication that shows where these different drugs sort of fall. You can see valrubicin kind of falls at historic, so that's what they used as a benchmark. And this line here is the International Bladder Cancer Group recommendation for three months and 12 months.

You can see that pembrolizumab, nadofaragene kind of straddle this line, so they're meeting the benchmark in some ways. NAI beat the benchmark for the first time. But then there's this big elephant in the room that people sometimes forget to mention. Of course, it's not a prospective trial that's been conducted. But remember, these are all single-arm studies.

And that's why when you say that we have gem/doce as the de facto standard of care in North America, I think we all need to pay attention to that and, in our minds at least, benchmark the approved agents against what's available, what's easily tolerated by patients, and what is actually fairly, fairly cheap compared to the cost of some of these other drugs.

Now, the IBCG put together a retreat last year to address the question of, well, we have all these drugs available, what do we do with the different sequence of drugs that we have? You can see here, pretty much anyone that's interested in bladder cancer is welcome to join, and they did. And we have many more that are in the acknowledgment section that are not authors.

This was the bottom line. It's in the manuscript. This figure is there. And in brief, I want to emphasize—and I did emphasize to trainees especially and young faculty—if you're offering bladder-sparing therapy to patients, make sure you stage them at each recurrence not to miss muscle-invasive disease or, of course, metastatic disease.

Then once you've decided that this patient can be offered bladder-sparing therapy, talk to them about radical cystectomy. Obviously, patients will likely refuse, but they need to know that that's the option. And then offer them a clinical trial because we still need to do clinical trials. We need that benchmark and that bar to go higher.

If the patient then does not want to participate in a clinical trial, currently, based on the data we have, we did recommend gem/doce as the primary treatment modality for patients with CIS plus or minus papillary disease. Of course, nadofaragene, NAI, pembrolizumab—all very good valid options. Pros and cons can be discussed with the patient based on timing, dose, et cetera, et cetera.

For those that have Ta/T1 disease, again, gem/doce came up as the primary recommendation. Then was nadofaragene, then hyperthermic mitomycin and single-agent chemotherapy were in the mix because these have shown efficacy. Now, we don't have these in the U.S., hyperthermia, but overseas and in other places, they do. And of course, then NAI and pembrolizumab, with pembrolizumab reserved for patients after they've exhausted other treatment options.

So this is it in a nutshell. There's many other recommendation statements in the manuscript that are here in the table. Obviously, I'm not going to try to go through this in the short time that we have.

But then to bring everything home, I wanted to remind the young faculty and trainees in the room, but all of us essentially, that patient-centric care is extremely important. We have to decide on treatment options based on what the patient wants.

And I would refer them to this global survey that we had done with the World Bladder Cancer Patient Coalition. Anyone can download the full survey, but it brings to mind in our mind what are the questions that are important to the patient.

The patient is asking, am I giving up long-term care for short-term gain? Do I still need to participate in clinical trials? What about every week coming to the doctor's office versus every three months? What about all this repeated testing and surveillance? Should I just have my bladder out? Do I need to go through cystoscopies? What about the cost to me, to my family, for the parking, all sorts of things?

So it's very important for us to remember that we are doing this for our patients and keep all this at the front of our mind. And with that, I'll stop, Zach, and happy to take any questions.

Zachary Klaassen: Yeah, phenomenal overview of a very, very great and really comprehensive talk you gave at the SUO. Just because I think there's so much to cover, we can unpack a lot. But with patient heterogeneity obviously at play, is there a favorite treatment in the BCG-unresponsive that you're using in your clinic right now, or is it really difficult to pinpoint that?

Ashish Kamat: No, I think obviously we have to personalize it to patients. But with all that being said, I think currently gemcitabine/docetaxel is something we have to discuss with the patient and we have to consider. The response rates are very promising. They're high. But we have to let the patient know that this is multicenter pooled data analysis. It's not a prospectively conducted trial.

And if the patient wants to then choose an FDA-approved drug amongst the ones that we have available, I talk to them about the relatively lower efficacy of nadofaragene but the ease of administration, right?

Zachary Klaassen: Right.

Ashish Kamat: So it's like, why not try this? And in three months, we'll know if it's working or not. And if it doesn't work, then we could try something else. NAI seems to have the highest response rates of the approved agents so far. So if a patient wants to go for the best efficacy, then NAI is my preferred option. But we have to remember we have to give that in conjunction with BCG, and many places don't have access to BCG.

Zachary Klaassen: Yeah, I think that three-month dosing of nadofaragene really is attractive to people, just like at your center and mine, people are traveling from four or five hours away. That is attractive, especially if we're going to keep giving these patients different treatments anyways, right?

Ashish Kamat: Right, exactly.

Zachary Klaassen: So you mentioned a couple of really exciting agents, EG-70, creto, et cetera. Is there one in particular that you're really excited about to see the data coming out for?

Ashish Kamat: I'm excited about all of them because they all have their pros and cons. So the nice thing about TAR-200, which is a device that's placed in the bladder, is that it's relatively easy for the patient because of the dosing interval, and the data look promising.

CG has good efficacy. And yes, it's a little bit more frequent and cumbersome, but it has good efficacy. And it's an immune agent, so you have that potential longer-lasting effect from that.

EG-70—again, early days because they don't have as many numbers of patients. But the delivery system is phenomenal because it's a non-viral plasmid delivery system. So you don't have to worry about a biologic hood. You don't have to worry about all the problems that go on with gene therapy, which is Adstiladrin, and nadofaragene of course, the generic name, and CG's cretostimogene. Those are viral drugs.

So EG-70 delivers the gene therapy, but there's no downside. You can just mix it up in the office with water and put it in the bladder. So they all have their place, I think, in the bladder cancer treatment armamentarium.

Zachary Klaassen: And you highlight it nicely. I mean, we have to be discussing radical cystectomy with these patients. You and I both take out bladders. In 2024 moving into 2025, who are you really pushing toward cystectomy after maybe primary BCG failure or one or two lines of therapy? Who's that patient?

Ashish Kamat: Yeah, I think this is a key thing, and we have a course at the AUA. I think the bottom line is that every time you want to consider if I do not offer radical cystectomy to this particular patient, am I going to kill him or her?

Zachary Klaassen: Right.

Ashish Kamat: Because we should have zero patients dying of non-muscle invasive bladder cancer in 2024, 2025. We should have better staging, which we do. It's not perfect, but we have better cystoscopy. Everything's improved. So today, for us to say, well, it's OK if 10%, 15% of people die and the other 85% are saved is absolutely wrong.

So at any point, if a patient has widely invasive T1 disease, has a lot of histologic subtypes, such as micropapillary or clearly small-cell or something like that, or if they have any suspicion that they've had multiple recurrences, now they're having hydronephrosis, if there's any suspicion that you are understaging these patients, it's really up to us to tell the patient, yes, on paper you have non-muscle invasive disease.

But there is sufficient data to show—and we and Pat Hensley have published this—that if you become muscle-invasive after being non-invasive, you have worse outcomes than someone who presents with muscle-invasive disease. So it's up to us, really.

And I'm glad you asked that question because one of my fears is that we may, as a community, start offering patients multiple lines of therapy and miss the window of opportunity to cure them. And then we have a patient who's like, I've kept my bladder in place but now have metastatic disease.

Zachary Klaassen: No, phenomenal message. You mentioned the IBCG paper. The IBCG has done some amazing work. I love that figure that you showed. I think what we all want is a test to say we should give this patient this treatment or that treatment or this treatment, the ultimate biomarker. Do you see one coming? Is it going to involve artificial intelligence? Where are we going with really trying to sequence these?

Ashish Kamat: Zach, if you had the answer to that, we could turn this recording off and cash in our multi-billion-dollar check. That's the key question. And I think it's going to be a combination of everything you just mentioned. It's going to be pathology. It's going to be AI pathology. It's going to be profiling the tumor, profiling the immune system, everything.

But bottom line today, there is no single test that allows us to do any sort of personalized medicine other than clinical parameters. So I think one thing that people tend to forget when they get enthusiastic about all of this, which they should, but they forget that grade and stage is still king. You can use grade and stage to make so many predictions and prognostications on patient outcomes that we shouldn't lose sight of using what's right in front of us.

Zachary Klaassen: Yeah, absolutely. Ashish, always a great conversation. Appreciate your time and expertise. Maybe just a couple of take-home messages for our UroToday listeners.

Ashish Kamat: Yeah, take-home message is every time you have a patient that has BCG-unresponsive disease, remind them that radical cystectomy is still in many ways the safest option. Stage them very, very carefully. Don't miss a T2 disease. Don't miss N1 disease.

And then, offer them treatments based on their needs and desires. There's no one-size-fits-all.

Pembrolizumab might be appropriate for someone who you think might have micrometastatic disease. Nadofaragene might be appropriate for someone that wants to come in only once every three months.

If someone says, hey, what's available that you would use that has good efficacy and low cost, well, it's gemcitabine/docetaxel. But also always remind people that we still need to do clinical trials. And yes, currently the trials are single-arm studies, and some patients have a question about that. But they will all get the treatment. And we believe that these agents will potentially keep raising the bar. So there's still a role for clinical trials, absolutely.

Zachary Klaassen: Awesome. Ashish, great conversation. Thanks again.

Ashish Kamat: My pleasure, Zach. See you shortly.

Zachary Klaassen: Sounds good.