Podcast Transcript: Managing Low & Intermediate Risk Bladder Cancer

[Dr. Amir Salmasi]
I agree with you. Again, the low-risk group, I'll tell them that it's going to come back, but most likely is not going to progress, "Is not going to something that going to kill you." Do you mean that going to be a personalized approach? I don't put anyone on just one episode of the one small tumor low-grade. I usually don't cysto them in three months. I do at least like six-month cysto unless they develop some symptoms, gross hematuria. Even they are old, I try to increase that interval because there's good data about the active surveillance on the low-risk small tumors.

If someone is old and frail, I'll tell them, we can just look at for a year, year and a half. It's personalized, but overall, as my standard is guidelines, I offer them six months cystoscopy and re-evaluate. If they have another recurrence, they change their class to the intermediate risk. Then we discuss about the adjuvant, the treatments into the bladder for one year. If someone comes with a DTS question from the beginning, I put in the intermediate risk group that have a multifocal disease or like a low-risk, a low-grade but there's a large tumor. That's different story.

If you want to be a little bit aggressive or more conservative approach, need to be on the treatment, like an intravesical chemo, induction, six weeks followed with the wealthy maintenance up to one year. If you want to wait to see another in three months and other episodes of recurrence, then you're going to go that path. I'm going to say, "There's no data. Compare to these two." I'll offer both of them. Of course there's a bunch of trials like you. At one point, we can discuss them.

[Dr. Aditya Bagrodia]
For the solitaries, all my counseling is very similar that we have two goals here to keep these from coming back, that's recurrence, and from progressing into more dangerous things like you all said, and I think prepping them so that if and when they have a recurrence, they're not like, "Oh my gosh, this is the beginning of the end." I tend to be more on the three months cysto for the solitaries because if they have a recurrence, most of the time you can just manage it in the clinic and save them an OR if it's a little bit bigger than you are, I think committed to the OR. Well,Betsy, in terms of the multifocal low-grade or larger low-grade that puts you in intermediate-risk category, any additions on top of what Amir said?




[Dr. Betsy Koehne]
No, I'll just echo what Amir said. For that situation, I would discuss with the patient pros and cons of doing an induction intravesical chemo course with typically gemcitabine. I don't normally push the patient if it's their first resection and they had multifocal low-grade TA. I usually just see how they feel. If they want to be more active, then we can do that, or if they want to just see how it goes, then I feel like that's fine too for that situation since there is such a relatively low risk of progression that we always have that tool in our pocket.


[Dr. Aditya Bagrodia]
I generally will give them all options, but at the end of the day, if you were my dad or my brother, whoever would probably just monitor and look in three months if they ask, "What would you do, doc?" Maybe it's the TA, the low-grade, small focus of high-grade, T1 low-grade that always is a bit of a weird entity, first off, a little bit challenging to believe just given the incidents. Anything of T1 low-grade? What do you guys think about that?


[Dr. Betsy Koehne]
I agree, that's not a typical diagnosis. Especially if it was from a community pathologist, I would definitely have that re-reviewed by a GU pathologist at my academic institution. Then if it was at my own academic institution, I'd probably just out of curiosity reach out to the pathologist because it is something that some people don't believe in.


[Dr. Amir Salmasi]
I don't believe in it too, but again, I don't know how we stage it or which category I put it. I don't think that low-grade cancer can invade the lamina propria, but if it's true, so which category it is, I don't know, that's like a challenge.


[Dr. Aditya Bagrodia]
I agree. Those are not super straightforward. I guess for the sake of completeness, small TA high-grade, what does that conversation look like, unifocal? Which would technically be intermediate risk per AUA guidelines?


[Dr. Amir Salmasi]
For me, I highly recommend patient receives adjuvant treatment. Maybe not for three years as a swab trial, maybe at least one year, and then highly recommend to elect from the Gem/Doce versus BCG. Again, we have a trial and you're our local PI, the bridge trial, push for it. I highly recommend even there's a small high-grade capillary to consider the adjuvant treatment.


[Dr. Betsy Koehne]
I would also use intravesical adjuvant treatment for that situation. I think also would depend on whether we were in a more acute BCG shortage time or whether there was BCG, about whether I would go with chemotherapy or BCG in that situation, but then also the patient's tolerance with Gem/Doce of having multiple installations and just spending longer in clinic. That's also something that I bring up with them when considering that.


[Dr. Aditya Bagrodia]
Is it fair to infer that if BCG were abundantly available, BCG would be the preferred intravesical option for a TA high-grade tumor? It would for me.


[Dr. Betsy Koehne]
Yes.


[Dr. Aditya Bagrodia]
The trial would be the preferred option, preferred, preferred. In the guidelines, it says intravesical immunotherapy or intravesical chemotherapy. If you're using chemotherapy, is this single agent gemcitabine? Is it Gem/Doce? Is it something else?


[Dr. Amir Salmasi]
For me is Gem/Doce. I don't believe in the single-agent chemo as adjuvant treatment. Only single-agent just for a perioperative time, but for induction and maintenance, I highly also recommend the maintenance of the combination of the Gem/Doce.


[Dr. Betsy Koehne]
I would also try to use at least combination Gem/Doce if we're doing chemotherapy for a high-grade tumor and [unintelligible 00:35:30].


[Dr. Aditya Bagrodia]
Maybe taking a step back, if it was a multifocal low-grade or a larger low-grade that puts you in intermediate risk, is that intravesical chemotherapy single agent or is it combination?


[Dr. Betsy Koehne]
I would typically start with single agent if they wanted to do intravesical chemo. You can always go up from there, but I think that's in the space where-- you're not usually going to lose any ground in terms of progression risk, so I think it's reasonable to start with less.


[Dr. Amir Salmasi]
You mean single agent as a preoperative treatment or just like you do as induction?


[Dr. Aditya Bagrodia]
No, like weekly gemcitabine, it's like a multifocal low-grade. [Dr. Betsy Koehne], I would agree with you. If they had like multifocal low-grade and they wanted to be aggressive and proactive, I would say, okay, we can do six weeks of induction gemcitabine and then monthly gemcitabine. Even that can be a bit of a debate depending on how everything went with the first go around for a low-grade.

If they progress, maybe we won't focus so much on that because I think that can progress to higher-grade tumors. That leads us into the whole conversation of BCG refractory disease. How about three months cysto and they didn't receive anything and now they've got multifocal low-grade tumors? Perhaps just for the sake of time, we completely resect those, whether that's a biopsy resection in the clinic or a trip to the OR. Now what? Now they're squarely in intermediate risk however they sort it out, right? Betsy, maybe we'll start off with you.


[Dr. Betsy Koehne]
If they hadn't had intravesical gemcitabine yet, I would just start with that. I rarely use Mitomycin C. I think I just grew up in the urology world where people were scarred by that, so I don't usually use it, although I have more recently seen people using it and saying that it's going okay. Then otherwise after that would see if we had a clinical trial open for another agent. Typically, I would just start with intravesical monotherapy gemcitabine if they hadn't had that yet.


[Dr. Amir Salmasi]
I think that for a patient with the intermediate risk, now we have more options. We can personalize the treatment, especially for example, someone older, you don't need to bring to the operating room as on the trial, chemoablation options, patient received surgery TURBT, we can discuss the adjuvant options. Adjuvant options can, again, as [Dr. Betsy Koehne] mentioned, be intravesical treatment, most likely intravesical chemo, or you can discuss clinical trials as adjuvant setting. If patient has a mutation, EGFR mutation, we can put the mulrise, the TAR-210 that releases erdafitinib and/or if you want to discuss the chemoablation that we do a resection, then you can talk about the UGN-102 that puts a gel with the mitomycin in the bladder.

I think the fields are going more and more discussion and conversation treatment upfront and the intermediate risk bladder cancer is going to be tailored towards a patient. If you look at this old lady, we don't want to bring you to the operating room on a frequent basis, maybe we go to the chemoablation or someone with multiple medical problem. There is no person that wants to receive more treatment. After that, we can always talk about the re-trial and mulrise or intravesical Gem/Doce.

[Dr. Aditya Bagrodia]
I think it is an exciting time where we're getting more options and perhaps thinking about this, let's just say that we're at a community practice without extensive access to trials or we're out in a not urban environment. The tools in our toolkit are monoagent chemotherapy, double A chemotherapy, gemcitabine, docetaxel, and BCG. Are those what you're thinking about as the current standards for somebody? [Dr. Betsy Koehne], you'd mentioned that you started out with single-agent chemo. If that doesn't work, what's your next kind of option for the patient?


[Dr. Betsy Koehne]
If monotherapy gemcitabine doesn't work and I have access to BCG, I would try BCG next. I don't know if the evidence can help us decide between doing BCG or a Gem/Doce next. I suspect either. I feel that either would be fine after monotherapy.


[Dr. Aditya Bagrodia]
Amir, what do you think?


[Dr. Amir Salmasi]
For me, if it's a little bit like a higher risk, like a multifocal, the larger tumor size, I'll go mostly toward the combination than monotherapy. If it's just like a small or papillary lesion, just a recurrent, I start with the monotherapy and then if no treatment. Either way, I don't think there's any strong opinion between the BCG or Gem/Doce.
[Dr. Aditya Bagrodia]
I agree. There's no nevers or always. For some of you that just hate using BCG for low-grade disease, it's like bringing a gun to a knife fight. It's based on nothing other than feels odd. God forbid they got sepsis or something. On the other hand, Gem/Doce, it's like, "Well, half of that combination didn't work the first time, so I'm not like beyond thrilled to use it." I guess if I have to land somewhere, I'll typically have to go Gem/Doce. If that doesn't work, and again, assume we haven't had the trials discussion yet, then go to BCG.

We are affected by the BCG shortages, so that's not the main driver here. I also just make sure that somewhere along that rhythm, I get repeat upper tract imaging to make sure they don't have some tumor up top that's seeding the bladder. Does this all sound reasonable? Anything you'd add on top of that?


[Dr. Amir Salmasi]
Yes. For me is reasonable.


[Dr. Betsy Koehne]
I agree. I think the clinic setting really affects whether it's easier to do Gem/Doce or BCG next. At the VA where I'm at now, we don't have docetaxel set up yet, so it'll be easier to just do BCG in that situation. In a few months, we'll have Gem/Doce set up, so then--


[Dr. Amir Salmasi]
Again, I feel like especially if you are talking to the community, doctors, urologists, I think the most important is like a risk stratification. As you said, the BCG is not going to work for people with a low-risk bladder cancer. We should stop overutilization of the BCG for a low risk. I think that's the first step, to get appropriate risk stratification. Based on that, then guidelines comes into play that BCG is not the treatment of choice for every bladder cancer.


[Dr. Aditya Bagrodia]
Okay. Let's talk a little bit about the trial. You mentioned targeted therapies, FGFR3 inhibitors, you mentioned chemoablation. Maybe we can at least spend a moment about that. Any familiarity with UGN-102? Does either of you all want to give us a little quick walkthrough what that is, how it's instilled?
[Dr. Amir Salmasi]
I can talk about the UGN. The delivery system is like a thermogel called RTGel. This gel when is in the cold temperature is a liquid, but it goes to body temperature, it just performs a gel and it stays longer time. Instead of just drain right away, it takes about six or eight hours the body get rid of this gel. When we put the mitomycin in this gel, we administer through the catheter into the bladder, it stays longer time, and over the six, eight hours, patient urinates and eliminates the drugs. The concept comes towards like a chemoablation.

We said if the people has like a small multifocal or immediate risk bladder cancer, are we worth that we give this treatment or we should go and surgical remove it? There was a two trial, they used like a Phase 3 trial. One of them was ATLAS trial. That was a randomized trial that compared to people receiving UGN-102, and if they had a recurrence, they go to take a transurethral resection. One was like a UGN plus/minus TUR and the control arm was just a TUR with no adjuvant treatment.

At three months, complete response rate in these two groups was similar, but the long term in 15 months, the people that receive UGN upfront had like a 72% response rate versus 50% of the people with the TURBT. There was some problem with this trial because they stopped early, the sponsor, because they want to try with different agent. It's not powered based on this patient that they recruited, but overall showed that a signal towards a better outcome of the people receive this UGN upfront, then they go TUR.

The other thing was like the people with the TURBT arm did not receive any adjuvant treatment. They did another trial, they envision was like a Phase 3, but single-arm, that all the people just received the UGN-102, and in three months, if they have a complete response, they follow it. Anytime they have a recurrence, start of a care, TURBT adjuvant treatment. Based on that also, they showed that very high complete response rate in three months after the UGN-102.

I think that it's going to be approved early in 2025 for the people with the intermediate risk bladder cancer that has like a multifocal small and then we think that maybe we don't want to bring for some reason to the operating room, or we discuss the patient or patient prefers that. One of this trial use UGN-102.
[Dr. Aditya Bagrodia]
Thanks. Thanks, Amir. I think it's exciting. It's really nice that there are companies paying attention to this relatively niche disease state. [Dr. Betsy Koehne], maybe I could just ask you to give us a little flavor for some of the trials that have you excited about next options for our patients.


[Dr. Betsy Koehne]
Amir mentioned earlier the erdafitinib pretzel, the TAR-210, which you also mentioned earlier, so about 60% to 80% of low-grade non-muscle invasive bladder tumors will have an FGFR2 or 3 alteration which we think is an oncogenic driver. Those are susceptible to erdafitinib. They initially looked at this in the THOR-2 study. There was an exploratory cohort in which patients had an oral dose of erdafitinib. That was a trial in which they left a marker tumor, so they did a TURBT, but left one of 5 to 10-millimeter tumor and then looked at follow-up. They had pretty good rates of response, but there was toxicity as it was a systemic treatment. Now they've been doing the TAR-210 with the pretzel.

|So far, I think at ESMO in 2023, they just had results from about 15 patients, but they had 87% with a complete response. It's a very early response rate, but I think that mechanistically it's exciting just that it's a great example of us learning more about the biology of the disease and applying a more targeted treatment. Hopefully, this would be very different mechanism. Maybe something will give us more lasting results.

Then I think I heard CG0700, which I can't remember the pronunciation for, but I think maybe SUO is doing the multi-site trial for that in intermediate-risk coming up.

[Dr. Amir Salmasi]
The other one is just Adstiladrin. Adstiladrin now also has an adjuvant setting for the intermediate-risk bladder cancer. If he patient has an intermediate risk, they receive quarterly of Adstiladrin that is an adenovirus that induces interferon, one of the elements of the immune response in the bladder. They had good results and the BCG unresponsive. Now they're bringing to the earlier stage and the intermediate risk. That one also patients like there's a randomized trial and if people on the control arm develop recurrence to cross over, they can receive the Adstiladrin. It's another interesting new trial, will be exciting trial.


[Dr. Aditya Bagrodia]
It kind of makes sense, right? It's like you start out with the BCG unresponsive and then it's BCG naïve for high risk, and now it's more like intermediate risk. It's a crazy thought. It's exciting that you have these tools in your toolkit for people with maybe non-life threatening but recurrent and highly inconvenient bladder cancer. It's also like a trip that they could be receiving medications that are literally like gazillions of dollars. I guess as things mature and perhaps get out of their period of being proprietary, et cetera, it's really cool to see these things and meet patients where they're at.

It's worth asking, I'm curious, have you guys ever done a cystectomy for recurrent low-grade bladder cancer?


[Dr. Betsy Koehne]
No, never.


[Dr. Aditya Bagrodia]
It's like you don't want to do that at all costs. I said BCG for low-grade seems wrong and a cystectomy for low-grade seems awful, but I don't discount how psychologically and physically challenging. Sometimes people get a TURBT and they're off for like a month and it's like a whole thing. It's nice to see these options. Here it is, we've been an hour talking about low-risk and intermediate-risk bladder cancer and want to be respectful of y'all's time. Perhaps, as we wrap up, any parting thoughts for the listenership?


[Dr. Betsy Koehne]
I would just echo what you're saying. I think even though for us as clinicians, and even though it doesn't really distress me very much about finding a low-grade or recurrent low-grade tumors, but I'm always reminded with my patients that it is something that is distressing for them. Just the recurrence and the anxiety around recurrence and the procedures, which even though we do them all the time, can still come with complications. It'd be great if there were no more super recurrent low-grade tumors. I hope that that's where we're going in the future.


[Dr. Amir Salmasi]
Yes, agree. I think despite that most of this group of people they're not going to progress, they're not going to die from the bladder cancer, but the cost of the treatment and doing the cystoscopies and all the surgery, tremendous on the patient over years and years and years. I think we need to find a way to-- the inter-supply treatment for the lower-risk people in this group. Again, it comes to the active surveillance for lower-risk group or some trials that we just do it, or biomarkers that prevents doing multiple cystoscopies.

There's lots of stuff, I think what we need to do for this two category. Despite that they are not going to die from this cancer, still it's going to have large impact on their quality of life and the hospital or health system.


[Dr. Aditya Bagrodia]
I couldn't agree more. One thing that just occurred to me in my last parting thought is I always tell patients and give them a Beacon brochure. It's a wonderful resource. I think it's a real top-notch educational and hope-inspiring community. Our local Beacon chapter, shout out to them, is beyond amazing. Providing their resources is a no-brainer. All right, Dr. Betsy Koehne, Dr. Amir Salmasi, it was a true pleasure having you all. Thanks for your insight on managing this and look forward to catching up at the SUO. Thank you.


[Dr. Betsy Koehne]
Thank you.