Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole, and we have two UAB physicians for you today in a panel focusing on non-muscle-invasive bladder cancer. Joining me is Dr. Jed Ferguson, he's a urologist and an Associate Professor; and Dr. Chas Peyton, he's a urologic-oncologist and an assistant professor.

Doctors, thank you so much for joining us today. And Dr. Peyton, I'd like to start with you. Can you set the stage for us about the scope of what we're discussing here today? The difference between muscle-invasive versus non-muscle-invasive bladder cancer in terms of natural history, disease recurrence, progression, and the people it most commonly affects.

Dr. Chas Peyton: Sure. Thanks so much, Melanie. So, bladder cancer as a whole is probably about the seventh, maybe sixth or seventh, most common cancer we see out there, and it's usually in the older population greater than 60. And 70% of bladder cancer is usually in men. Now, bladder cancer can be broadly divided into muscle-invasive disease, which is potentially a fatal disease, life-limiting, or non-muscle-invasive disease, which is usually non-fatal, but can progress to muscle-invasive disease, and has a major problem with recurrence.

In this specific podcast, we're going to be talking specifically about non-muscle-invasive bladder cancer, which means that cancer is not penetrated through what's called the lamina propria, so the spongy tissue right above the muscle. Specifically, you know, like I mentioned, the biggest problem with non-muscle-invasive bladder cancer is recurrence. The disease comes back and back and back. And the more recurrence you have, the greater the proportion or likelihood of progression you can see when patients aren't treated.

 The main standard of therapy of non-muscle-invasive bladder cancer has to do with transurethral resection of these tumors, one for diagnostic and treatment purposes as well as intravesical therapies. Mainly, the therapy we most commonly use for treating non-muscle-invasive bladder cancer is called BCG. It's actually a derivative of tuberculosis and part of the cell wall polysaccharide is quite immunogenic. And so, we actually give this medicine into the bladder for a standard series of treatments, and it causes a robust immune response within the bladder. And that prevents the tumor from recurring or progressing.

However, the medicine's been around for 40 years, but it still has a lot of struggles because it's only, you know, 60-70% effective in long term. So, recurrence is quite an issue. And it also causes a number of urinary symptoms and problems as people move forward with repeat resections and repeat medicines in the bladder. I'm not sure if Dr. Ferguson wanted to add anything to the background of what we're talking about today.

Dr. Jed Ferguson: One of the biggest challenges for non-muscle-invasive bladder cancer, and by the way, we can separate non-muscle-invasive into low grade and high grade, based on how aggressive the cancer looks under the microscope. Fortunately, low grade is more common, and easier to deal with just with transurethral resection of bladder tumor with lower recurrence rates. But high grade is really problematic because if BCG doesn't work, then, historically, patients were out of options and we were really focused on bladder removal as our first-line recommendation for what we called BCG-unresponsive high-grade non-muscle-invasive bladder cancer.

And there's been some really exciting movement in the field recently that has opened up some options for patients to allow them to keep their bladder. And UAB is really at the forefront of bringing patients into trials in that space.

Melanie Cole, MS: Well, thank you both for that. And Dr. Ferguson, since you see these patients at the start, maybe they start with primary care and then make their way to Urology, what are they presenting with? And how is it different in non-muscle-invasive bladder cancer from muscle-invasive? What do you typically see when you first see a patient?

Dr. Jed Ferguson: Yeah. The usual presenting diagnosis is blood in the urine or hematuria. Most of the time this is blood in the urine that patients can see, so gross hematuria. But sometimes it's a urinalysis that was obtained for other reasons, and they see some red blood cells under the microscope and that's called microscopic hematuria.

So, overall, about 20% of patients with gross hematuria end up having a diagnosis of some malignancy in the genitourinary tract, mostly bladder cancer, but also kidney cancer and urothelial cancer of their upper tract. And then, about 3% of patients with microscopic hematuria will have cancer of the genitourinary. Very rarely, it's a bladder mass that's seen on a CT scan that's obtained for other reasons, but that's pretty rare.

Melanie Cole, MS: Okay then, so Dr. Peyton, when we think of what used to be the traditional treatment options, what used to be done and how has that evolved now?

Dr. Chas Peyton: Non-muscle-invasive bladder cancer has had an explosion of treatment options recently. So, like Dr. Ferguson mentioned, the disease routinely recurs and then can progress. So, bladder removal surgery was the mainstay of treatment, and still to this day. Bladder removal surgery is the best option for a cure, but not necessarily best option in terms of Surgical risk, quality of life, and various other things having a major operation. So, like I mentioned earlier, the medicine, BCG, has been around for ages and it's a fairly effective medicine to prevent this tumor from coming back in the bladder, and again, it's delivered into the bladder.

The problem that we see today with BCG, the biggest problem with BCG is, you know, there's side effects and whatnot, is actually the availability of the medicine. BCG is remarkably challenging to make, and not to get on a different soapbox, but there's actually only one company currently in the U.S. that makes this medicine and the margins for that medicine are really limited. So, as any other company would go tell you, their ability to produce it depends kind of on the margins. And the margins are so bad that they don't really like to make it. They have to, but for that reason, there's a major supply and demand problem.

So for that reason, there's been other trials recently on Intravesical chemotherapy, which is certainly an option. And we do that. It's completely off-label from the FDA, but that doesn't really matter. We've seen pretty good effectiveness from combination intravesical, meaning in the bladder chemotherapy with gemcitabine and docetaxel, which is a really pretty good option.

And then beyond that, there is a plethora of newly developing, very exciting medicines to be put in the bladder and given systemically to help treat with this disease. We won't go through all of them, but they range in different mechanisms of action, ranging from kind of oncolytic targets or viral vector targets and even targets to further rev up the immune response. Even more exciting recently, there's actually a device that's been developed to be placed in the bladder to secrete chemotherapy over a longer duration of time. And that is actually with the FDA right now.

In terms of FDA-approved therapies, there are few. There's some older ones that we won't even mention because they're not effective. But the most, the recent one is what we call nadofaragene firadenovec. It's a mouthful. But it's basically gene therapy to increase the uptake in expression of interferon alpha within the cell, which promotes immunogenic responses to treat the tumor. And I'll let Jed kind of comment on some of the other newly developing medicines we have, because there's plenty.

Dr. Jed Ferguson: Yeah. So, in 2019, the FDA approved the first non-cystectomy treatment for BCG-unresponsive, and that was intravenous pembrolizumab, which was very exciting in that it was the kind of first in niche medication. But I would say that most of us have been fairly disappointed by the efficacy, and the therapeutic ratio. So, it has about 15% adverse immune events, and the mortality rate from complication ending in mortality happens in about somewhere between one in 100 and 1 in a thousand patients. So for a non-lethal disease, that's really a risk that a lot of patients are unwilling to take.

So, it's Adstiladrin, or nadofaragene firadenovec is much safer than pembrolizumab. Still, the one-year complete response rates are only about 30-40%. So, I think most of us, it's better than taking your bladder out, but we're not curing a majority of patients with that therapy. And then, there's some other immune therapies that are currently coming down the line. Some of these, we're starting to see 12-month complete response rates that are much higher than what we currently have available in the 60-70% range. So, those data are, I would say, immature at this point, but very exciting to all of us that take care of patients with bladder cancer.

Dr. Chas Peyton: I'll just comment, there's a lot of new data in this space, and all these trials are up for approval at the FDA level right now, and they've done enough to get approved for FDA. But the durability, long-term durability of some of these medicines, we don't really know.

Just to tell you a few of them, you know, there's the medicine called Anktiva that's given with BCG. There's another medicine called cretostimogene. And then, there's the TAR-200, which is the intravesical device that I mentioned earlier. There's a few others we won't talk about. But long story short is over the last 10 years since we had a FDA defined reason or FDA definition of what we call BCG-unresponsive non-muscle-invasive bladder cancer, we've had an explosion of new therapies. But the long run on how effective these are in the long term, we don't know yet. But again, it's an explosion of options that we have this day and age to treat this, problem.

Melanie Cole, MS: Well, let's discuss some of those. Dr. Ferguson, what's really exciting going on right now as we think of new treatment options and what you see happening in the future? What's really exciting in your field right now?

Dr. Jed Ferguson: The new medications that Chas just mentioned, I think, are incredibly exciting data coming out of these preliminary results with complete response rates in the 60-70% range. So, in patients allowing them to keep their bladders. Especially with the TAR-200, I'm personally very excited about that because it really opens up the field to retrying a bunch of the old chemotherapies that we had assumed were ineffective and actuality was probably because you were instilling chemotherapy liquid into a bladder, bathing the cells for an hour, and then the patients were urinating it out and you were expecting the chemotherapy to work within an hour. It's expecting a lot. So, now we have this system that allows us to put any drug we want and to spill it over days to weeks, such that the pharmacokinetics are going to be a lot better, and I think their response rates are going to be a lot better. So, it's a very, very exciting time.

Dr. Chas Peyton: We've had all these trials, Melanie. And one thing we've learned-- I would say, what I would tell you what's exciting is we won't go into the mechanisms and actions of all these because it's complicated and probably not for this listenership. But we've learned over the last decade that we can treat high-risk non-muscle-invasive bladder cancer that's failed BCG, with various other medicines and really safely delay disease recurrence and progression such that what we thought at one time was not safe, meaning having these high-grade disease come back and back and back and we just do the cystectomy and remove their bladder, we've seen that we can safely watch these patients, and we can safely treat these patients without a cystectomy for years.

And so, that's been a really exciting thing to see with all these trials. And, like Jed said, the medicines are novel. They're new mechanisms of action that have never been tested before. And, personally, I think the long-term effectiveness is out for debate. However, the cream will rise to the top, so to speak. And in my opinion, what's going to be probably the best treatment for these is going to be the treatments that is most easily distributed to providers. Some of these medicines like nadofaragene firadenovec are incredibly expensive, they're hard to deliver, and the dosing schedule sometimes is difficult. Whereas if you have a medicine that can sit on your shelf and doesn't require chemotherapy hood for delivery or technical problems and delivery, that medicine's probably going to be better taken up by the community and by everyone, even if the effectiveness rate is not as good.

Melanie Cole, MS: Isn't this so interesting? And what a great dynamic you two have. It's an exciting time in your field as it's moving so quickly. I'd like to give you each a chance for a final thought here. So, Dr. Peyton, tell us about any clinical trials that are available at UAB Medicine and what are on the horizon and what you see happening in the future.

Dr. Chas Peyton: Thanks so much. So yeah, at UAB, we have a number of clinical trials available for non-muscle-invasive bladder cancer. The first one that's quite exciting is a very simple question. As I mentioned, BCG is a standard, but a non-FDA approved method that we've used for years is intravesical combination chemotherapy. And so, the first trial we have is for patients that have newly diagnosed intermediate or high-risk non-muscle-invasive bladder cancer, they're either randomized to get BCG or intravesical chemotherapy upfront. And that is a great trial. It's going to answer a lot of questions for us.

The second trial we have available at UAB is for folks with what we call BCG-unresponsive, non-muscle-invasive bladder cancer. We have the option of giving them the systemic pembrolizumab that we mentioned earlier, or what's also known as Keytruda plus intravesical chemotherapy. So, this is combination therapy, so systemic, and within the bladder.

 And then, upcoming trials that we are going to be opening shortly, one is with a company called enGene, where we're looking at some more modifications in the bladder in terms of immunotherapy and gene therapy to treat BCG-unresponsive non-muscle-invasive bladder cancer. And another one called the TAR-210 study, which is a different device, which is an intravesical device that secretes a medicine called erdafitinib.

So, there's a lot of other trials we could talk about out there. This is a very hot space for clinical trials. Those are just a few of the things that we have open at UAB. In the future, like I said, these trials are going to all prove some degree of efficacy, but really the ease of treating these patients is going to be really important.

Melanie Cole, MS: Dr. Ferguson, last word to you, what would you like the key takeaways to be from this episode and this discussion today for other providers? What would you like them to know about what you're doing there at UAB Medicine?

Dr. Jed Ferguson: I think the key takeaway right now is it's a very exciting time for high-grade non-muscle-invasive bladder cancer. We have a variety of new treatment options that have been FDA approved and a variety of new treatment options that are undergoing registration with the FDA right now based on really exciting data.

So, a very exciting time to be in the field and, I think, right now we have to really focus on how do we sequence all these new therapies and how long can we let patients keep their bladders, and that's something that they're all going to be very excited about.

Melanie Cole, MS: Thank you both so much for such an enlightening discussion. Thank you for joining us and for sharing your incredible expertise. And for more information, you can always visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole. Thanks so much for joining us today.