High-Grade BCG-Unresponsive Bladder Cancer Management & Alternatives

[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. For 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. 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.

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[Dr. Tim Clinton]
I typically would counsel I don't think that's a treatment failure by any accounts for BCG. I typically just try to explain to them that at the BCG is really good at eradicating high-grade disease and the biology of a low-grade tumor is a little bit different. 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.

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[Dr. Tim Clinton]
If this is a situation where I'm truly worried about these patient's concerns. I think there are 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.



[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 cystectomy. 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. Aditya Bagrodia]

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?

[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.
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[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.