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BackTable / Urology / Podcast / Transcript #64

Podcast Transcript: Management of BCG-refractory NMIBC

with Dr. Timothy Clinton and Dr. Eugene Pietzak

In this episode of BackTable Urology, Dr. Aditya Bagrodia speaks with two fellow urologic oncologists, Dr. Timothy Clinton (Brigham and Women’s Hospital) and Dr. Eugene Pietzak (Memorial Sloan Kettering), about the management of BCG-refractory non muscle-invasive bladder cancer. You can read the full transcript below and listen to this episode here on BackTable.com.

Table of Contents

(1) BCG-Unresponsive Bladder Cancer Criteria and Patient Classification

(2) BCG Intolerance

(3) BCG Dosing & Duration Considerations

(4) Side Effects Following BCG Treatment

(5) CIS vs. BCG Cystitis Work Up & Management

(6) BCG Management for Ta High & Low-Grade Carcinomas

(7) T1 High-Grade Bladder Cancer Management

(8) Alternative Management To Cystectomy Following BCG Treatment

(9) Pembrolizumab Monotherapy Indications & Recommendations

(10) Upcoming Clinical Agents for Treatment of NMIBC

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Management of BCG-refractory NMIBC with Dr. Timothy Clinton and Dr. Eugene Pietzak on the BackTable Urology Podcast)
Ep 64 Management of BCG-refractory NMIBC with Dr. Timothy Clinton and Dr. Eugene Pietzak
00:00 / 01:04

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[Dr. Aditya Bagrodia]
Hello, everyone, and welcome back to the BackTable Podcast, your source for all things urology. You can find all previous episodes of our podcast on iTunes, Spotify, and at backtable.com. This is Aditya Bagrodia is your host this week, and I'm very excited to introduce our guests today, Eugene Pietzak, from Memorial Sloan Kettering Cancer Center, and Timothy Clinton from Brigham Women's. How are you guys doing today?

[Dr. Eugene Pietzak]
Doing well. Excited to be here. Great to see you both.

[Dr. Tim Clinton]
Thanks so much for having us.

[Dr. Aditya Bagrodia]
Yes, it's a pleasure and I’m excited. I've had the good fortune of spending time as a trainee with both Eugene and Tim, and we go back and share fun memories and war stories from fellowship at Memorial in residence at UT Southwestern. Eugene has now converted to the other side as an attending, but thrilled to have you on today. We're going to talk about BCG refractory muscle-invasive bladder cancer.

[Dr. Eugene Pietzak]
I was going to say, I have had the distinct pleasure of training under both of you.

(1) BCG-Unresponsive Bladder Cancer Criteria and Patient Classification

[Dr. Aditya Bagrodia]
That's right. Yes, that's like a double-whammy tip. No wonder you're not even an assistant professor yet. This is a topic that I think can be confusing in my experience. As an academic urologist, a lot of mismanagement can take place for this group of patients, but maybe let's just start out with some definitions. When you're thinking about BCG-unresponsive bladder cancer, can you just walk us through the lexicon of pertinent terminology?

[Dr. Tim Clinton]
Sure, I can start. I think BCG-unresponsive disease has been a difficult one to characterize, and I think the best definition these days and the most widely accepted has been defined by the FDA in 2018, with their BCG-unresponsive criteria for clinical trial design. They've really defined this as folks who have had adequate BCG, which includes five of six induction courses, and two or three maintenance doses of BCG, or five of six induction BCG doses, as well as, I believe two of six of a second induction course as well. If they've undergone adequate BCG and have persistent or recurrent CIS within 12 months, recurrent high-grade Ta or T1 within six months of adequate BCG or T1 at the first evaluation, and this is what we now define as BCG-unresponsive disease.

[Dr. Aditya Bagrodia]
When you say T1 at the first evaluation, the patient comes in, T1 high grade, you do your resection, you do repeat resection, they don't have any pressing indications for a upfront early, timely cystectomy. You do induction BCG, and then you take a look in their bladder and there's T1 high-grade recurrence. How would you define that patient?

[Dr. Tim Clinton]
I think this is exactly what we're talking about as far as unresponsive disease. Now, this is somebody that I'm worried about. They had their first induction course of BCG, you're starting to talk about invasive disease that's still present. Now, I'm starting to talk about early cystectomy and possible alternative therapies at this point.

[Dr. Aditya Bagrodia]
Technically, per the FDA, does this patient have BCG-unresponsive disease? They've just received their induction course not a five plus two, or you're saying just after the very first induction here?

[Dr. Tim Clinton]
Yes.

[Dr. Aditya Bagrodia]
Oh, right. right. Yes, exactly. First evaluation after adequate BCG for T1. This is somebody-- but I still am worried about it. They still have T1 disease, now we're looking at, is this someone who's still going to potentially respond to a second induction course or not.

[Dr. Tim Clinton]
Yes, I guess what I'm getting at is, to me, the FDA definition is interesting in some ways. It's these patients that you really worry about that they get their induction course and they've got persistent or worrisome disease multifocal T1 high-grade, or diffuse carcinoma in situ. I feel like, in my mind, I think of them ultra high-risk players that should be eligible, say, for like a clinical trial, or something a little bit more involved. For these patients specifically, I would counsel towards a cystectomy. Eugene, what do you think? Is that patient unresponsive per the FDA definitions?

[Dr. Eugene Pietzak]
Yes. Per the FDA definitions and for clinical trial purposes, they certainly do fall into that category of BCG-unresponsive disease, just of induction course only, and then having on your first three-month assessment high-grade T1, that would meet the criteria. I agree with both of you, this is definitely a concerning situation that we run into, but I think a lot of us at academic centers, think the FDA criteria provides a very good framework and tries to develop this more homogeneous cohort for which we could do clinical trials.

I think we also need to be mindful that the BCG unresponsive criteria is really just based off of expert opinion, it wasn't super data-driven. There's been some post-hoc analyses to validate it, but you think if we've been using BCG since 1976 or so, there's over 40 years of data. I think it would have been nice if we would have got together, pool their data sets and come up with a more evidence-based definition. I think the framework that we have now is helpful, and we're not going to go back, we're going to go forward.

Pembrolizumab is FDA-approved. There's a handful of other agents that I'm sure we're going to talk about that will likely get FDA-approved. I think when you're faced with that patient in clinic, though, you have to think about where his initial treatment was. Where were the TURBTs performed, because there's tremendous variability. The BCG-unresponsive criteria for clinical trials doesn't factor in that initial tumor management, whether or not a restaging TURBT was actually performed or not. I think that's very relevant when you're in that three-month assessment.

I think it's hard to tell, is this biologically resistant disease, or was this patient just had disease that went unresected, because they didn't have a restaging TURBT locally, and now you're seeing this patient post-BCG. I'm still worried about that patient because as Tim had mentioned, these are early invasive changes, and this can be a very biologically aggressive tumor. What we see in clinical practice and what the clinical trial criteria are, may not necessarily always merge.

[Dr. Tim Clinton]
Totally. I think this is a role for the enhanced cystoscopies, whether it's enhanced cystoscopy in the office or the blue light TURBT. At the time of your repeat resection here, I think that plays a role too. The initial management was as a blue light or enhanced cystoscopy at the time of the TURBT. Certainly, if you're doing it now, post-BCG, I think this all helps you just make sure that you've had a thorough analysis and all tumor was resected.

(2) BCG Intolerance

[Dr. Aditya Bagrodia]
Yes. We've jumped on into it, and I had an outline and I think this is just great. We've covered some definitions. BCG intolerance, is this something that you guys, encounter? I get calls from our infusion center that patient X was only able to hold their BCG for 10 minutes, and they're having significant and frequency and urgency bladder spasms. Is this a common clinical scenario? Well, actually, what do you tell your patients that are about to start their first course of BCG? What's the probability that this is going to work, and then what does BCG look like?

[Dr. Tim Clinton]
Sure, I think when I'm talking to folks who have had their initial TURBT, and I think you had your initial podcast with Dr. Sam Chang there who did a really nice job of discussing what constitutes an adequate evaluation and adequate transurethral resection of a bladder tumor. I think that's probably the most important thing as we've alluded to already. After that, now they have some amount of high-risk or intermediate risk, non-muscle invasive bladder cancer and you're discussing the options for BCG.

I tell them that we're going to start with an induction course of BCG, which will be given once a week for six weeks, followed by a rest period and then an evaluation usually about 12 weeks after the initial resection. That BCG is a medication here that's instilled into the bladder and it's truly an immunostimulatory agent here, and so because of that, your body has a systemic immune response as well and can actually induce changes within the bladder, but also some systemic side effects as well.

I tell a lot of folks that I expect some amount of dysuria urinary frequency urgency shortly after the administration and there can even be flu-like symptoms for about 48 to 72 hours after the administration of BCG but in general, these are self-limiting and should resolve. Additionally, these side effects can sometimes be a little bit worse after the first couple of doses for BCG. It'll get a little bit worse during the treatment while they're undergoing treatment with BCG. But then after that, we'll assess their bladder. There are certainly some folks who can't tolerate BCG. I think you're mentioning someone gets the BCG and it's just too painful or the side effects are too much and they can't tolerate further doses despite local control. Then these are the folks who you, you can subsequently deem BCG-intolerant.

[Dr. Aditya Bagrodia]
Eugene, when they say, "Doc, what's the chance that this is going to work for me? How do you have that conversation? Maybe we could start out with patients that have papillary high-grade tumors and then patients that have CIS and then combination patients. You've done their most recent TURBT and feel like you've cleaned them out.

[Dr. Eugene Pietzak]
Yes, I think as you alluded to, I do give a stage-specific or disease-specific estimate based off the data, at least the way that I interpret it. Someone who has say high-grade T1 multifocal disease with diffuse CIS, those patients, I counsel and emphasize that there's a little bit of concern depending on whether or not you're worried about potential clinical under-staging. Potentially even if you're doing it yourself, et cetera. Those patients I'll counsel like the chance that they would derive clinical benefit from BCG may be as low as 50% sometimes.

Certainly, that's an opportunity for clinical trials of BCG plus initial agent, maybe like an immune checkpoint inhibitor in that case if they have early invasive changes, et cetera. For a patient with papillary high-grade Ta only disease, those patients chances of response I typically quote them is at least 80% or so. Those that don't initially respond, may be able to be re-challenged with a second induction course or again, a clinical trial opportunity. Those patients may still derive clinical benefit from BCG that can be long-lasting.

I do counsel patients though that even if they have an initial response, even with maintenance BCG, there's still a chance that they could recur. Typically I say somewhere around 20 to 30% chance within the first few years. Again, I try to individualize it a little bit more patients with multifocal disease, even if it's high-grade Ta, I worry more about those patients with larger tumor burden overall. Even if they're fully resected using enhanced cystoscopy techniques, et cetera, compared to a patient a small solitary tumor. I think risk-stratified my estimates to them.

[Dr. Tim Clinton]
Yes, that sounds about spot on or consistent with what I do. If it's the favorable end solitary Ta, high grade, less than three centimeters in that 80% range. Now you're getting on the other end of the spectrum T1 high grade. Usually if they have LVI, I'm super worried but if it's T1 high grade and not chock-full unresectable early cystectomy candidate closer to about 50%.

(3) BCG Dosing & Duration Considerations

[Dr. Aditya Bagrodia]
Couple of questions. Both in terms of tolerance of BCG maintenance regimens and our ongoing BCG shortages, that's certainly something we're affected by. We get a weekly email and it's like, "Oh my gosh, like we're about to run out of BCG." First question on that first counseling session, how are you advising your patients in terms of duration of maintenance BCG, and then do you ever use dose reductions, and what are your opinions on that?

[Dr. Tim Clinton]
I think you're exactly right. We're all plagued by this BCG shortage right now, which is really become terrible as far as patient expectations with regards to especially to maintenance BCG. Here, we're certainly keeping a list of everybody who's eligible for BCG treatments, whether it's induction or maintenance, and priorities given to those who need induction courses. Certainly if you have T1 or CIS disease, these men and women are at the top of the list for that induction course.

I tell everybody that that's the most important course of the treatment and maintenance if we have extra available will be given. Again, preferences given for those for the first maintenance course and the second maintenance course but it really is dependent on what our shipment is for the month there. We've been doing one-third dose reductions based on a couple of different studies and I think MD Anderson and Ashish Kamat's group have done a nice job of showing the efficacy of one-third doses as well.

[Dr. Aditya Bagrodia]
Eugene, how long is a patient in your practice typically going to get maintenance BCG?

[Dr. Eugene Pietzak]
I typically give or try to give at least one year of SWOG protocol maintenance, BCG 3, 6, and 12 months. Then depending on the availability of BCG at that point in time we may go to try to go for the full three years. I think as Tim had said, it's more important to prioritize the induction and we typically will prioritize full-strength induction course BCG rather than one-third dosing. With a caveat that some of my partners with discussions with their patients often will not give maintenance BCG.

I think if you go back to the original studies of that and look at that, not everyone necessarily derives clinical benefit from the maintenance BCG. There's probably about a 25% benefit in recurrence-free survival, potentially a benefit for progression-free survival, but at least the SWOG clinical trial use that composite point of disease worsening. I think ideally patients will receive maintenance BCG and it's supported by the guidelines, but I think if you have a limited supply of BCG, that should definitely be allocated for induction courses.

If I could go off script just for one second and put a plug for an upcoming ECOG study, The BRIDGE trial, that's going to be randomizing patients with newly diagnosed NOMI invasive disease, high-grade disease between BCG versus gemcitabine and docetaxel. I think as a community, that's going to be such a critical study to support such an important trial to support as a bladder cancer community since BCG has been the first-line option for over 40 years. Gem/Doce as we'll probably discuss later on has some promising data.

This is an ECOG-led study by Max Kates at Hopkins that should hopefully be opening within the next few months.

(4) Side Effects Following BCG Treatment

[Dr. Aditya Bagrodia]
Yes, couldn't be more excited. Honestly, our GU oncology consensus here is if we get to dire straits with BCG, we're going to shift to Gem/Doce first line and yes, familiar with the trial. I think it's great. It's an awesome trial. It's a big trial. It's an ambitious trial, but I do think gemcitabine and docetaxel has been plagued by lower-quality evidence, which is why it's not a part of our FDA-approved armamentarium in the BCG refractory space. Of course, we'll talk about that. Fantastic.

I think I've got a good sense of how you counsel patients on what your likelihood is of responding and what BCG looks like. A number that stuck out of my head for the three-year maintenance program. The SWOG trials that only about 20% of people actually completed that. Now whether that's they lost interest or it was persistent side effects, it does seem that there's two camps like there are for so many things. People that do just fine with BCG, no issues, no problems.

Then the other end of the spectrum are going to be the people that they really have the fatigue, the systemic symptoms, the pelvic pain discomfort. One of the things that I've started doing is actually for all my female patients that are getting BCG is starting them on vaginal estrogen. I feel like their vestibulodynia and discomfort has improved. I think that might be something that could be beneficial. Then I've also had a handful of patients with extreme, what I would consider BCG cystitis.

At their three-month or six-month cysto their bladders just look terrible. I'm super worried that they're chock-full of tumor, resect them, and it's all cystitis. For some of these patients, actually been once I've confirmed that there's no recurrence, having them receive hyperbaric oxygen therapy but just a couple of things that I've been doing. Any opinions or have you seen any of these patients where you look in their bladders and they just look inflamed, angry, erythematous, telling dyscrasias everywhere?

[Dr. Tim Clinton]
It's really interesting what BCG can do. I actually had a patient recently who was getting treated for another secondary malignancy, but had a PET scan and his prostate lit up, which had BCG granulomas throughout it, biopsy. I've had patients with epididymitis orchitis from the BCG, right? It just is so inflammatory sometimes. You're exactly right. The bladder itself can get really cystitis everything else. I think you have to utilize some other therapies to try and get them through the BCG therapy or just switch course to a different treatment option.

[Dr. Aditya Bagrodia]
Even more reason to support The BRIDGE trial, toxicity, BCG shortage, et cetera. Now--

[Dr. Tim Clinton]
Are you guys using any-- we rarely get to the maintenance courses for these guys. We're running through our BCG for induction courses and very rarely getting enough doses for maintenance these days. I think talking to other folks, at least in academics and certainly in the community, very few people are doing maintenance doses due to the shortage.

[Dr. Eugene Pietzak]
Yes, our maintenance literally earlier this month got X’d. We were at full-dose induction, one-third maintenance for up to a year. They had to have high-grade, high-risk per weight guidelines. Now it's just induction and it's tough. The patients don't like it and I don't like it. Nobody likes it. I've actually gone to some gemcitabine docetaxel maintenance, which is a little atypical, but-- Well, we started doing the same here. You can judge--

[Dr. Tim Clinton]
No, no, we're doing it too.

[Dr. Eugene Pietzak]
Go ahead and judge but it's like something seems better than nothing.

(5) CIS vs. BCG Cystitis Work Up & Management

[Dr. Aditya Bagrodia]
All right, now let's just jump into that three-month system. Let's walk through some clinical scenarios. You look in the bladder and it's erythematous and they've got a history of CIS. First things first, you get a cytology and it's positive. What's your next step in this scenario? Office biopsy OR biopsy, is a cytology enough?

[Dr. Eugene Pietzak]
Cystosing erythematous lesions concerning for possible CIS versus BCG cystitis and the cytology is positive. I personally will take that patient to the operating room and under sedation at least do biopsies and fulgurate. I am a bit of a believer that I think there is a therapeutic benefit from trying to at least fulgurate some of the CIS and I do especially areas where it looks like there could be some early papillary changes. I will formally resect those areas safely at least.

Then once in a while, you'll see that there is some lamina propria involvement. Usually, it's focal and it's a small amount, but I think that's important to know because that is a concerning feature. If the cytology comes back negative, unless I'm very worried about the patient, I don't often take biopsies. I would probably just proceed with roundup maintenance BCG and then reassess it six months. The concerning aspect of that is we know that many patients based off the SWOG maintenance clinical trial data will convert to a complete response, but not everyone will.

Then they would by definition at that point meet the definition for BCG-unresponsive disease having received induction plus maintenance and the standard of care in 2022 is still radical cystectomy. It is unclear to me whether those patients would've done better if they would've received a full and second induction course of BCG. We do have a clinical trial here where we're combining BCG with intravesical gemcitabine for patients who you would typically retreat with BCG. Trying something a little bit different and hopefully getting better results.

[Dr. Aditya Bagrodia]
Yes, perfect, Eugene. That's pretty similar for me. If I take a look and it's not overly concerning, I'll tell the patient, "Listen, if the cytology's positive, we're going to do a biopsy. If the cytology's negative, we'll continue on with BCG." If the cytology is positive that patient, depending on their comorbidities, maybe I'll just put that out there. We'll either get an office biopsy or preferably an operative TURBT. If it shows carcinoma in situ at that biopsy or operative resection fulguration. How are you going to manage that patient? Three-month cysto biopsy-proven carcinoma in situ after induction BCG.

[Dr. Tim Clinton]
For me, my standard of care option would be actually a full induction course, a second induction course of BCG. As I alluded to, we have a clinical trial option as well as BCG plus alternating doses of intravesical gemcitabine because although some patients-- the SWOG maintenance randomized data would suggest that about 50% of patients would convert from a non-responder with CIS to a complete response at their six-month assessment. 50%, it's essentially a coin toss more or less.

Hoping that either that full six weeks of BCG or that clinical trial as I alluded to, and I think there's other clinical trials that will probably be, that are assessing BCG plus immune checkpoint blockade, et cetera. May see if there may be better efficacy with a combination. Although personally, we'll talk about this in a bit, I always have a little bit of concerns about the toxicity for an immune checkpoint inhibitor.

[Dr. Aditya Bagrodia]
What if their cytology's positive and you don't biopsy prove any persistent cancer? Does it take a little while for the cytology to seroconvert? Are you worried, are you doing urethral biopsies and random bladder biopsies and blue light cystostomy, ureteroscopies, selective cytologies? Are you going for broke or how do you synthesize that?

[Dr. Tim Clinton]
I think post-BCG there is a role or at least the guidelines do state the possibility of utilizing some other markers as well, such as UroVysion FISH and ImmunoCyt or even CxBladder, which everybody seems to be hot on. We are not utilizing any of these, I don't think it changes management given those current tests. For myself, if someone has a positive cytology, you go and you biopsy, you don't find anything that's still residual just continue with the maintenance BCG courses at that point. I'm not doing anything extra.

[Dr. Aditya Bagrodia]
Eugene?

[Dr. Eugene Pietzak]
Yes, I would agree and I think as you suggested, do the same alluded to, I typically will take prosthetic urethra biopsies as well as selective cytologies for patients. If their bladder looks like there's obvious carcinoma in situ I typically will not because those will almost always be positive and probably just contamination. I'll still probably do a sampling with a prosthetic urethra in males because I do worry for someone with diffuse CIS that there's some stuff hiding out there. I'll do full TUR loop biopsies from five to seven at least.

As just like Tim said, if the biopsies all come back negative and the prosthetic urethra's negative, I will often counsel patients that CIS by definition doesn't really adhere very well and it's not uncommon to find denuded mucosa. To me, if you have a positive cytology and you have denuded mucosa, it's just indicative that the CIS cells are being shed into the urine and I think in that situation maintenance BCG would be totally reasonable.

[Dr. Tim Clinton]
Yes, I agree and I totally hear you on the biomarkers. Atypical cytology I think is, especially with auto-release of results and no context is something that's concerning for patients. There is data on anticipatory positive FISH and so forth but ultimately I subscribe to the memorial philosophy that, are you going to do anything different? The short answer is typically not, whether their FISH is positive or an ImmunoCytor a CxBladder.

(6) BCG Management for Ta High & Low-Grade Carcinomas

[Dr. Aditya Bagrodia]
Great. CIS biopsy-proven basically gets a second induction of course if there's anything remarkably concerning that can be tailored. If it's a positive cytology without biopsy-proven continuum with maintenance, the patient could be counseled that if they're getting a second maintenance instead about a 50% response rate. That sounds about spot on. What if they've got something papillary and it's a Ta high-grade?

[Dr. Tim Clinton]
After BCG, I think as I mentioned earlier, I do all of these with blue light cystoscopy. Now we don't have it available in the office, but I think we're talking about already in the OR. This is where I would do a blue light transurethral resection of a bladder tumor to ensure that I get all of that papillary tumor out and anything surrounding it. I routinely see that there's either other tumors that were not seen on the white light cystoscopy in the office on the surveillance cysto. I do think there is added benefit and has been shown as well with blue light cystoscopy.

Or if you alternatively don't have that available and you utilize narrowband imaging, I think that's equally acceptable. It's your enhanced cystoscopy of choice, if you will, I think are very, very important. These patients, if they're recurring already after BCG, you want to be as thorough as possible getting all of that papillary tumor out. If it's just Ta high-grade, again, we proceed with a second induction course at this point.

[Dr. Aditya Bagrodia]
Eugene?

[Dr. Eugene Pietzak]
Yes, I would agree with what Tim said. In terms of some high-quality TURBT using enhanced cystoscopy. I'm a little bit more selective in blue light and the patients that I do that in routinely, but typically will do narrow band imaging just to, in my own personal experience out of 50 or 60 initial patients assessing blue light the clinical benefit of it. I didn't find to be any better than narrow band imaging but with that aside, I think doing a high-quality to TURBT identifying additional papillary tumors. Then once that is fully resected, then I would definitely retreat them with BCG if they have non-invasive disease. I think that's consistent with the AUA guidelines.

[Dr. Aditya Bagrodia]
Now, just for the sake of completeness, what if they have actually Ta low-grade after their induction?

[Dr. Tim Clinton]
I typically would counsel I don't think that's a treatment failure by any account for BCG. I typically just try to explain to them that the BCG is really good at eradicating high-grade disease and the biology of a low-grade tumor is a little bit different. For those patients, if they demonstrate that they have a low-grade recurrence, at least the initial one, I will typically post BCG do in the operating room. If they continue to have low-grade recurrences, which some patients do, those are things that I worry a little bit less about in terms of managing that in the office potentially with full duration if they're pretty small.

Always try to do a biopsy on those patients if they had a high-grade Ta tumor at initial diagnosis or so. I worry a little bit less about those patients that have these low-grade recurrences post-BCG.

[Dr. Eugene Pietzak]
Yes, the low grades ones I'm not so worried about.

[Dr. Aditya Bagrodia]
Would you keep them on maintenance?

[Dr. Tim Clinton]
I would, Yes. because again, I don't think that's a treatment failure. I think the BCG did its thing and eradicated the high-grade components.

(7) T1 High-Grade Bladder Cancer Management

[Dr. Aditya Bagrodia]
Then there's the T1 high grades. Diagnostic resection, rep nephron resection, induction BCG, three-month cysto, papillary tumor, you resect that it's T1 high grade. What does that conversation look like?

[Dr. Tim Clinton]
If this is a situation where I'm truly worried about these patients concerns. I think there's a lot of factors that go into it. Both the tumor characteristics, multifocal, extent of lamina propria involvement. Is it multifocal? Is it extensive or is it minimal invasion? Is there associated CIS. All those tumor factors go into it, but also patient factors are very important. Is this a young and healthy male or is this a very comorbid individual that may be not the best cystectomy candidate? I think a lot of that goes into those discussions.

Whether I'm particularly worried about this patient and counseling more towards an early cystectomy, or is this a patient that probably would be better served with an additional attempt with bladder preservation, even if they're at a higher risk for progression?

[Dr. Aditya Bagrodia]
Right. Of course, it's not cookbook and there's patient desires, patient comorbidities, disease characteristics. Let's start out with maybe like the one end of the spectrum, nodular multifocal LVI extensive and they're willing to receive a cystectomy. To me, that's a no-brainer next step.

[Dr. Eugene Pietzak]
Yes, I would agree, and LVI is so uncommon in high-grade T1. That's a patient that I'd be really worried about and potentially even counseling that they may have nodal involvement and may need systemic therapy typically. At least in my experience, that would be after cystectomy verifying the pathology stage, verifying the nodes, but I know that there are some centers that advocate potentially for systemic therapy, even for these very high-risk T1 patients. I don't know if that's necessarily indicated or beneficial and I think the data is weak overall on that.

Whenever you see a variant histology LVI, these very high-risk features, I think definitely counseling those patients towards discectomy. I just worry we have very few effective bladder-preserving options after BCG has failed, and I think it's such a major unmet need and cystectomy is curative in the majority of these patients.

[Dr. Tim Clinton]
The one other thing I'll add is, and maybe you'll get to this later, but the variant histology for these T1 high grades also puts you into that high-risk category there. Especially if the invasive component, our pathologist here will read it as the invasive component contains sarcomatoid or any of those other sorts of features, this is definitely concerning, certainly pushing me towards cystectomy for that patient.

[Dr. Aditya Bagrodia]

Yes, so a couple of things. I definitely think it's a good idea to stage them. I would get a CT scan chest, abdomen and pelvis personally if they've got persistent high-grade disease, T1, high-grade disease after induction BCG because you can have lymph node metastases or so forth in that clinical setting. By all means, Tim we didn't even have the upfront cystectomy conversation. T1 high grade with LVI sarcomatoid features, variant histologies, unresectable, et cetera, but totally point taken. It sounds like the preference would be cystectomy and totally agree with that. Now, what if the patient's unwilling or unfit to receive a cystectomy, what's your next go-to option here?

(8) Alternative Management To Cystectomy Following BCG Treatment

[Dr. Tim Clinton]
Yes, for us with these recurrent T1 high grades after BCG unwilling or unfit for a cystectomy, this is where you're looking at other alternative options now. If they're meeting the criteria here for BCG-unresponsive disease, you have a couple of different options. Our current preference at this point is the utilization of gemcitabine and docetaxel intravesical. FDA approval currently is just for valrubicin and pembrolizumab.

[Dr. Aditya Bagrodia]
Yes, comprehensively, the way I think about it is we have cystectomy, we have pembrolizumab, we've got Gem/Doce, we've got of course clinical trials. Valrubicin is an FDA-approved agent that I don't even really bring into the conversation. Then there's the stuff that's coming through the pipelines I think is exciting. Again, second induction course of BCG would be of those, and this is an opinion in this patient with large volume recurrent T1 high grade. While I am generally a fan of Gem/Doce, to me, I'm not super keen on another intravesical option, necessarily, if they've got a lot of early recurrent tumor. I would actually maybe lean toward pembro, but I'm curious to see what you all think.

[Dr. Eugene Pietzak]
If we're talking about our super high-risk, very high-risk T1 patient here, I think another potential option because this is a patient we're concerned that may have clinical under staging. I would completely agree that I would be uncomfortable with an intravesical option in this, although it's only been published in abstract form at this point. There is the chemoradiation potential option for some of these patients. I do discuss that for patients that I feel that they probably do have muscle-invasive disease even though clinically they're T1 and I counsel them as such.

The energy data is abstract form. Honestly, I'm not that super enthusiastic about it, but I think there's robust data from muscle-invasive disease. Whether your early T1 post BCG would behave differently I think is a little bit unknown. but I do think that's an option for these very high-risk T1 patients for sure. For your run-of-the-mill high-grade T1 with BCG-unresponsive disease without significant multiple risk factors. At least my belief is that we should be supporting clinical trials first.

For these high-grade T1 patients, I do think that adding that systemic component that you had mentioned pembrolizumab, but the KEYNOTE-057 data certainly wasn't anything to write home about. I like these ideas for the clinical trials that are combining immune checkpoint inhibitor with an intravesical agent, the Alliance trial, that's pembrolizumab plus intravesical gemcitabine for example. For high-grade T1 patients, I tend to preferentially recommend that clinical trial or clinical trials like that with the systemic component.

Where for patients that may just have CIS or high-grade Ta, BCG-unresponsive disease, those may be patients that are better served with a intravesical-only treatment option and avoiding the potential immune-related adverse events with an immune checkpoint inhibitor.

[Dr. Aditya Bagrodia]
Yes. Thank you, Eugene. That's an excellent point. I think for a variety of reasons, sometimes chemoradiation doesn't come up, case in point, I didn't even mention it, but I think you're absolutely spot on. While it's not a home run and many of these patients are probably going to have fairly significant lower urinary tract symptoms, it may not be the best option, but point well taken. I think this really digs into when you look into somebody's bladder, you either, something goes off that says, I'm worried or I'm not worried.

When you're worried, it is like cystectomy systemic therapy, and when you're not worried, you feel like you could try something gemcitabine docetaxel and you're not going to miss an opportunity of a window for cure. We talked about CIS in a second induction course of BCG Ta high-grade not concerning. Is that going to be a second induction course of BCG patient for you?

[Dr. Tim Clinton]
Yes, exactly. If they've only had a single course of induction BCG with a recurrence of Ta high-grade, then they don't technically meet the criteria for BCG-unresponsive disease yet. This is the time when I'm giving them a second induction course of BCG.

[Dr. Aditya Bagrodia]
Now we're looking at either the patients had a second induction course or induction plus maintenance and they've had a high-grade recurrence and you're running through it. What does that conversation look like with the patient? What's your spiel?

[Dr. Tim Clinton]
Any amount of a high-grade recurrence after adequate BCG is certainly concerning. I think it's never too early to start engaging in the idea of early and timely cystectomy just to put it on the table. For somebody who maybe it was difficult for them to get through those, just an induction and a maintenance course at BCG, the thought of undergoing any further intravesical therapies is pretty dissuading to a patient. They're ready to just get everything out. I don't think that's unreasonable.

If it's really just superficial single Ta lesion or something like this, now we're talking about really more second-line intravascular options. I tell them that, while the first-line option was BCG and unfortunately, they've had a recurrence, we have some other options available that seem to have pretty promising data. For us, we do lean on gemcitabine and docetaxel, and we've had pretty good success with it. Again, it's all based on retrospective data, so we do have to take that into consideration. At this time, these are easy drugs to get. They're cheap. In the absence of other clinical trials, which I also would get into, that's our second-line therapy at the moment.

[Dr. Aditya Bagrodia]
Eugene?

[Dr. Eugene Pietzak]
I agree with what Tim was saying. I think, early on, having a discussion and introducing the concept of radical cystectomy in these patients that you're worried about, I think that's pretty important. I think emphasizing a lot of the quality of life data that is now emerging, suggesting that patients do go on to live healthy, fulfilling lives after cystectomy, and it is at this point in time, in 2022, the only real curative option after BCG fails. I think introducing that idea early on is important.

What I like about non-muscle invasive bladder cancer is you tend to develop relationships with patients as they go through multiple lines of therapy, et cetera. At least putting that on the back table, so to speak, as you go through the different bladder-preserving options, but my typical approach is BCG. If BCG is not working, then typically clinical trials, and if there-- well, cystectomy discussion versus clinical trials, and based off how worried I am about that patient.

If they're not eligible or not excited about the clinical trial options that are available to them, then our default option has also been the gemcitabine-docetaxel combination as well. I think I share both of your feelings that although it does seem promising, the data, the evidence is pretty weak and retrospective to support it. I do worry. I'm sort of heavily influenced by Richard Feynman with the quote that, "The first thing is not to fool yourself, and we're the easiest people to fool."

I do worry that maybe this combination of gemcitabine and docetaxel may not be that much better than single agents. I think the science behind it, or the combination makes sense to me, and that's what we do for metastatic and muscle-invasive disease, but it will be nice to get some high-quality data to support what we're doing clinically.

(9) Pembrolizumab Monotherapy Indications & Recommendations

[Dr. Aditya Bagrodia]
Perfect. What about pembro FDA-approved? Are you excited about it? Do you feel like it's doing something for the sake of doing something, when the patient comes back with pneumonitis and colitis and their fingers have autoimmune off you like, "I helped you"?

[Dr. Eugene Pietzak]
I think it needs to be discussed with every patient because it is, besides valrubicin, which isn't really that readily available, it is the only FDA-approved drug. I think, at least in my practice, it always comes up in a discussion, mostly as an option. But because we have the availability to enroll on clinical trials with a component that has intravascular gemcitabine, I do send my patients with BCG-unresponsive disease to meet with a medical oncologist. They'll discuss pembrolizumab as a monotherapy.

Very rarely does the patient to actually opt to go on that, but it's more for the discussion of pembrolizumab within the context of a clinical trial, or any immune checkpoint inhibitor within the context of a clinical trial. I think the data isn't very compelling. It's great that it was FDA-approved, but you know, it's a 40% response rate at three months, and beyond 12, 18 months or so, only about 20% of patients remain disease-free. I have a slide with a table on it that basically, with the expected response rates for the various options that are available to patients. Many patients will even decline meeting with a medical oncologist because neither one of us is very enthused about the potential results with pembrolizumab monotherapy.

[Dr. Tim Clinton]
Our medical oncologists are not very eager to be giving pembrolizumab to a lot of these patients as well, for the associated toxicities. They're actually pretty strict about it too. The FDA approval was only in the KEYNOTE-057 publication that's thus far been published has only been in CIS disease, with or without concomitant papillary disease. They're pretty strict about which patients they would even consider giving pembrolizumab to because of the fact that only about 20% had that clinical response, or complete response beyond 12 months. It doesn't even really meet some of the prior goals of the FDA as far as complete responses at 12 months.

[Dr. Eugene Pietzak]
I think there would be a little bit more enthusiasm if there is a biomarker-driven approach to this. I think the unselected patients, not the risk-benefit tradeoff between these immune-related adverse events and the marginal benefit that patients receive. I think the math unfortunately isn't in the favor of treating many of these patients, but if there was a biomarker to select these patients, I think that will definitely be very beneficial. Unfortunately, the publication, PDL-1 staining wasn't beneficial, wasn't helpful.

Hopefully, there is some work ongoing from the result from the KEYNOTE-057 cohort, and other work is ongoing, but until that happens, I think there's going to be a lack of enthusiasm as a urology community, at least.

(10) Upcoming Clinical Agents for Treatment of NMIBC

[Dr. Aditya Bagrodia]
Yes, I think you're absolutely right. At this point, I'll typically start looking into things like tumor sequencing when I'm getting worried, and we can certainly envision a day where ultra patients would go on to something like erdafitinib. It's exciting, right? It's exciting that over the course of our careers, and we're not 1000 years old, we've seen these new changes, new options. I remember being at a dinner during residents with the Valstar people and just being like, "Oh, my gosh, I wouldn't even off this." It's disappointing, we get 10% response rate.

At least we have some other options now. We're coming on about an hour. It's been an amazing conversation. Clinical trials have come up, and I don't think we're going to be able to comprehensively run through all of them. Eugene's mentioned of IO, intravesical therapies, which I think are exciting. There's novel treatments, instiladrin, and things along those lines, there's the devices. Maybe I could just ask both of you all to share a couple of thoughts on what you're excited about.

[Dr. Tim Clinton]
You're right. There's so many options coming down the pipeline. There was even Vicinium, of course, which I think failed to get FDA approval. Now, with adstiladrin coming on, and I think they're seeking FDA approval. There's so many agents that are looking to advance in this space. I do think that there's a lot of renewed excitement, maybe is the idea, of some of the agents that you can put into the bladder. The pretzel, I think was popularized for a while there, and coming back online. There's just so many different agents, so I'll be interested to see what ultimately wins out.

To echo some of what Eugene said as well, I think the biomarker-driven strategy, whether it's a urinary-based assay, or if it's truly tissue-based, both would be exciting as far as helping guide maybe a little bit more precision-based treatment options for a lot of these patients, because I think there is a heterogeneous mix, even in the non-muscle invasive space.

[Dr. Aditya Bagrodia]
Perfect. What do you think, Eugene?

[Dr. Eugene Pietzak]
We run through the clinical trials that bubble up in some of our own thoughts, and Jelmyto and the bladder. There's all kinds of things that are out there that are being purposed and repurposed, as you've mentioned.

[Dr. Aditya Bagrodia]
Have you ever heard of a CD20 agonist?

[Dr. Tim Clinton]
This is the Bernie Bochner trial.

[Dr. Eugene Pietzak]
It's anti-CD40 inside of Rockefeller. It's a clinical trial that we're running in Phase I. The preclinical data looks very promising.

[Dr. Aditya Bagrodia]
I agree with both of you in terms of there's a lot of things coming down the pipeline, and I think that is exciting, but it also presents challenges to us as a community as well. I think when you have almost a limitless number of agents and potential combinations, I think we as a community need to be thoughtful how we're going to do this. I think it's important to generate high-quality data that we can potentially assess. I completely agree with the idea that a lot of this should be biomarker-driven, within high-grade T1, within CIS, et cetera.

There's a lot of tremendous heterogeneity in terms of the biology of the tumors themselves. I think there's only a limited number of patients, it's certainly those that are going to be enrolling on clinical trials. I think some of these larger, more ambitious trials, unfortunately, are closing because failure to accrue. I think we need to be pretty thoughtful in how we develop these clinical trials or assess these drugs or combinations more quickly and more accurately. Whether that's a urine-based approach using urinary tumor DNA, et cetera, whatever it may be.

Get an idea, "Is this drug or this combination promising or not? Or, is the toxicity acceptable?" Because some of these systemic therapies are acceptable and patients with metastatic disease are going to be very willing to accept some of these toxicities. Someone with non-muscle invasive disease, when cystectomy is curative for these patients, they're going to be less tolerant of some of these immune adverse events like we have been discussing. I think moving forward being able to rapidly assess these drugs and combinations is going to be even more important.

I think in terms of therapies that should be readily available in the near future. I think the N-803 combination with BCG, that data looks fairly promising. Maybe this is just the skeptic in me in total. You got to wonder since BCG-unresponsive disease is just based off expert opinion, we actually don't know how the BCG alone would perform in some of these patients. I think some of these patients may derive benefit from BCG, not suggesting that they receive it, but I wonder how much of that efficacy we're seeing is from the actual IL-15 superagonist versus from the BCG retreatment. Not to end on sort of a down note, but I think a lot of that data may be generated in this BCG naïve trial that they're running comparing this combination versus BCG.

[Dr. Tim Clinton]
Yes, I think you brought up a good point was just that as we're looking at all of these trials that are coming down the line, ultimately we'll have to compare them head to head. We keep using these tables and looking at response rates at 3 and 12 months. We have to actually compare these head to head ultimately in sort of better trial designs ultimately. I think you're exactly right.

[Dr. Eugene Pietzak]
Yes, 100% agree with you. I think BCG unresponsive criteria is very helpful in sort of building some momentum to these single-arm trials and coming up with things to potentially test. Cross trial comparisons are fraught with a lot of issues. Again, not to end this on a downer, but I also do worry that like some of the data that we're seeing may be more of a natural history type of situation with BCG-unresponsive disease. The fact that instiladrin, the fact that pembro, insineum, et cetera, we're seeing like a 40 to 50% initial response rate.

Then seems to all drop down to about 20% beyond 12-18 months or so. That has me a little bit worried. Some of that may be therapeutic effect from TUR as suggested a believer in that. That's why I think the N-803 plus BCG data, that seems more promising. Maybe there is a little bit more activity there than elsewhere, but I agree 100% that the only way to know that is to compare some of these agents head to head. It's just if you were a patient or for your own patients, like would you really want to be randomized to pembrolizumab? I think investigator choice randomization is also a little bit challenging or presents some challenges.

[Dr. Aditya Bagrodia]
No, I can not interpret any of this as being overly skeptical or negative or pessimistic. I think what I'm hearing here is we have to remember that BCG-unresponsive disease is a dangerous clinical state. What we don't want to have is a litany of options where it's like, here's first line, here's second line, here's third line, here's fourth line, here's fifth line. That's an accepted way to think about it and you miss an opportunity of a window for a cure because you've let things go.

We've had this discussion when you're worried and when you're not worried and how that frames it but just because there may be six different FDA-approved options, it doesn't mean that they're going to sequentially continue to work or that you may miss an opportunity of a window for a cure if you continue messing around with either intravesical or systemic options. Personally, it's been really fantastic to see the work you guys have done to help us understand some of the molecular features of these tumors.

You're leading clinical trials, you've been thought leaders and I've certainly learned a ton. Thanks for your time. It's been amazing catching up and picking your brains. I think the future is bright.

[Dr. Tim Clinton]
Thanks so much, Aditya.

[Dr. Eugene Pietzak]
Yes, thank you so much.

Podcast Contributors

Dr. Timothy Clinton discusses Management of BCG-refractory NMIBC on the BackTable 64 Podcast

Dr. Timothy Clinton

Dr. Timothy Clinton is a urologic oncologist with Brigham and Women’s Hospital in Boston, Massachussetts.

Dr. Eugene Pietzak discusses Management of BCG-refractory NMIBC on the BackTable 64 Podcast

Dr. Eugene Pietzak

Dr. Eugene Pietzak is a urologic oncologist with Memoral Sloan Kettering in New York City.

Dr. Aditya Bagrodia discusses Management of BCG-refractory NMIBC on the BackTable 64 Podcast

Dr. Aditya Bagrodia

Dr. Aditya Bagrodia is an associate professor of urology and genitourinary oncology team leader at UC San Diego Health in California and adjunct professor of urology at UT Southwestern.

Cite This Podcast

BackTable, LLC (Producer). (2022, November 9). Ep. 64 – Management of BCG-refractory NMIBC [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.

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