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Zachary Klaassen: Hello UroToday. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined on UroToday by Dr. Vignesh Packiam, who is a urologic oncologist at the Rutgers Robert Wood Johnson Medical School in New Jersey.

Today, we'll be discussing optimizing patient selection and treatment timing for emerging intravesical therapies.

Vig, thanks so much for taking time out of your busy day to discuss this awesome topic on UroToday.

Vignesh Packiam: Of course, yeah. Really appreciate you having me. I think it's a really exciting time for patients and urologists. We have so many great treatment options now for patients and we're soon to get more too. So we'll talk about how do we optimize patient selection with having so many options that are out there? And are there aspects of timing for some of these that are relevant for when we're making those decisions?

So I'll go through a case. This is a very standard patient, 74-year-old male, average age for bladder cancer, and obviously has a male predilection as well. This patient has BCG-unresponsive high-grade disease. They received induction BCG and their first maintenance. And right after that, they had a recurrence with multifocal CIS and high-grade Ta disease. So unfortunately, this is not that uncommon of a situation to find ourselves in.

Like many patients, this patient has some LUTS already. Frequency every two hours, nocturia times three. As patients get older, they already have some baseline lower urinary tract symptoms. And from repeated TURBT or intravesical therapy, a lot of the time that becomes acute on chronic worsened situation.

This patient does not have significant comorbidities and he lives two hours from the hospital. My prior job was at University of Iowa. We had patients that would travel 2, 3, 4 hours. I think it's very regional for how long patients are traveling. But even in New Jersey, even if patients are closer to us, there's traffic. There's different things going on. So common problem for patients to have to travel a bit to get to the center that they're going to.

So always good to start with definitions. So BCG-unresponsive is a definition that was primarily used to help the FDA define patient subsets in their clinical trials. For most of the groups of BCG-unresponsive disease, you must have received adequate BCG. So that's also known as the 5 plus 2 rule, at least five of six induction, and at least two of three maintenance, or two of six of a second induction. This patient has received adequate BCG.

If you have high-grade papillary Ta or T1 disease recurrence within six months of last BCG, that's one criteria for being BCG-unresponsive. Our patient fits the second criteria CIS within 12 months of last adequate BCG. And then the third category is a patient with T1 disease immediately following induction.

Any other categories are BCG-exposed. And there is some data suggesting that patients with BCG-unresponsive disease have worse outcomes than those that are BCG-exposed, which is why we have prioritize our focus in that setting.

We have a whole slew of options now, and there's more coming down the pike, which is exciting. I'm just going to blaze through some of the pluses and minuses of each of these. So valrubicin is an intravesical chemotherapy that was approved over 25 years ago. We don't use it that often, because it's relatively toxic and it has poor, durable efficacy. But more than 20 years after that, pembrolizumab was approved in 2020. This is an intravenous checkpoint inhibitor.

Anytime complete response was 41%, but the one-year complete response was less than 20%. And when we look at the fact that over 10% of patients have grade 3 or greater adverse events, sometimes even permanent, there's not many urologists that recommend this treatment option for patients. But in a patient that really has trouble with retaining intravesical therapy, this could be a nice option in that select circumstance.

Adstiladrin, this is an oncolytic adenovirus that was approved in 2023. It basically turns the BCG into an interferon-alpha production engine, if you will. This was approved in 2023. One-year complete response was 24%. Anytime complete response was 53%. This is one of the few agents that actually has long-term data for it. They recently published their five-year outcomes.

And it's reassuring that progression is relatively low, well tolerated. Grade 3 or greater adverse events is less than 5% And it's a very, very easy to use medication. It's given quarterly. So the induction is actually just a single treatment, which is unlike any other therapy that we have. We almost always give once a week for six weeks. And then the maintenance also continues in that once-every-three-month pathway. So there's not a lot of treatments patients have to get if they're starting with this therapy.

Anktiva was FDA approved in 2024. This is an IL-15 superagonist that's combined with BCG. You literally just mix the vial into BCG and you give it exactly like you give BCG. Their are anytime complete response was above 60%, one-year complete response was 45% with the caveat that in their study, they did allow for reinduction.

So on my calculations, based on the data that's available to me, about half of the complete responses at one year did receive reinduction at some point. So take that into account when we're comparing it to other trials. They don't quite have as long-term follow up published yet. So I haven't seen five-year data for their agent. But progression still relatively low and very well tolerated, less than 2% grade 3 or greater adverse events.

Gem/Doce has been around for a while. This is not FDA approved, but it is used pretty widely off-label. First published in 2015, and all of the data for it is retrospective, which is different than the other studies that are on the table here. One-year complete response was 60% So I think a lot of people, when they see that number, if they have access to give Gem/Doce at their clinic, which not everyone does, it's a good option to at least talk about with your patients.

We do have five-year outcome data published for Gem/Doce. Relatively low progression rates, well tolerated, just like the other intravesical therapies. Main negative of it is the logistics. Patient does have to sit in the office for two back to back instillations so it can be a couple hours.

So we have that nice of menu of treatment options. And there's more that are coming with some exciting clinical trials that are out there.

How do we choose? There's a lot of different factors that we look at. So efficacy, that's the easiest one for people to fixate on. These high CR numbers look really good. It's tempting to make off-trial comparisons. I would argue it's actually not as important when you're comparing all these different treatment options. It's interesting that when you look at reported efficacy rates over time, especially in the newer clinical trials that are coming out there, it just seems to get better and better over time.

So is it really true that all of these treatments are really getting better over time, or is patient selection a factor? And I think one thing that illustrates this really nicely is when you just look at BCG. So Dr. Catalona put out some pretty classic data back in the 1980s, that if you give repeat induction BCG over and over again, it stops working over time. So that's what the definition of BCG-unresponsive is based on. After a patient has received a certain amount of BCG, additional course of BCG is very unlikely to work, 20% or less.

Fast forward to now, Amanda Myers and Ashish Kamat just put out a very thought-provoking paper this last year. They had a small cohort of patients with BCG-unresponsive disease. They gave additional BCG to those patients and the one-year complete response was greater than 70%. So how can that be? The patients are getting the identical BCG that they did before. Is it really that it's working better, or is our overall treatment paradigm better?

We're doing better cystoscopy with blue light. We're doing more aggressive re-resections. We're doing routine re-resections with T1 disease. I think it's a little bit of both. So I think it's really challenging to compare efficacy between different trials because there's so much selection bias that you can't control for.

What about safety and immediate tolerability? For the intravesical therapy options that we have right now, they're actually pretty comparable. If you look at Adstiladrin, Anktiva, Gem/Doce, a lot of these grade 3 or greater adverse event rates are relatively low. They're less than 5%. So they're well tolerated.

When you look at the actual tolerability of holding the medicine inside the bladder, anecdotally, they seem pretty similar. And from what you can glean from the clinical trials, they all have the same kind of intravesical lower urinary tract symptoms, bladder spasms, dysuria, those types of things. So again, it seems pretty similar between the different treatments.

What about long-term tolerability? I think this is a totally underexplored facet of what the patient is experiencing. When we look at the clinical trial data for all of these agents, the CTCAE profile, that's a good way to characterize especially systemic therapy for medical oncology interventions. But for intravesical therapy, it's a little bit crude and it doesn't really capture what's happening long term.

So I can honestly say we don't have great data telling us what's a patient's bladder going to be like after two years of Gem/Doce versus two years of Adstiladrin or Anktiva or anything else. And I think that we really have to study this more.

Logistics of delivery I think is very important. And that is a nice differentiator between the different treatment options that we have right now. And I would say of the available treatment options, I'm a huge fan of Gem/Doce. I write about it all the time. I talk about it. But the logistics aren't perfect.

I think the clear winner for logistics, when you look at these available options, probably would be nadofaragene, or Adstiladrin, with the quarterly instillation. I think that's a big benefit for patients that are driving a far distance to come in to see us, and if they're just trying to get less instillations, less catheterizations, I think that's a really important factor.

So again, focusing a little bit on nadofaragene here, who's the right patient and when's the right time to give it. I think if a patient really is trying to minimize travel and logistics of coming in, it's a good medication to consider. There is some new interesting data showing that the real-world efficacy is better than what was initially reported in the clinical trials.

And again, that goes back to my point about not necessarily splitting hairs about direct efficacy comparison. I think a lot of these treatment efficacies are getting better over time, just because of our better surgeries and our better management overall. And I think it's to be determined what the long-term tolerability is. That's something that we're doing some research on and I think others are as well. It's really an underexplored question.

But this treatment may have an edge just due to the fact that you're getting less catheterizations, less instillations. And I'm sure that that is favorable for the bladder. Thank you.

Zachary Klaassen: Great discussion. Lots of great jumping off points. I love that table you had because it really lines up all the options that we have. And as you mentioned, this space is just going to get busier and busier over the next 6, 12 to 18 months.

Focusing on the nadofaragene, I think you made great points about travel logistics. In your patient experience, if you just hear what the feedback is, what is their experience with it day of instillation? How do they like that three months? What is the patient experience in your clinic?

Vignesh Packiam: Yeah, it's a really good question. I think some of it is prefaced by what we're doing differently to get the patients ready for this. So since it is a once-every-three-month instillation, I actually put a lot more effort into making sure that the patient tolerates it compared to something like BCG, where you can afford to see how they tolerate it and then give them interventions based on how they do. Some patients do tolerate these medicines well.

So Adstiladrin, I'm routinely checking urine cultures before every single instillation, which I don't necessarily do for other intravesical therapies, especially on maintenance. I do routinely give them some type of anticholinergic or beta 3 agonist leading up to the instillation, just to make sure their bladder is maximally relaxed.

Oftentimes, I'll give a day of Pyridium also, getting right up to the instillation. If they have any trouble with the first one, one thing I do for all intravesical therapies is that I'm quick to give things like Ativan or sometimes even in our low-dose narcotic. A lot of the spasm issues sometimes can be fixed with just decreasing patient anxiety and giving them a more calm situation. So I found that to be helpful sometimes.

And then the last little trick. This was actually developed by one of the APPs at University of Iowa. Gravity instillation technique can be helpful if someone has a really spastic bladder or small capacity bladder. That's where we put the catheter into the bladder, instill the medication. And then instead of just clamping the catheter, we hook it up to a Foley bag, hang that on an IV pole. So if the patient has a bladder spasm, the medicine refluxes up the tubing and comes back down. So these are all little things that we can do.

What is the actual patient experience? A lot of patients say it's similar to BCG. It's a little bit of an inflammatory medication. And most of these patients have had BCG in the past. So that's the main feedback that I've gotten about it.

Zachary Klaassen: Excellent That's great. I think you mentioned the long-term bladder quality of life. I think it's going to be huge because we're probably doing less cystectomies. We've got better options. So I think it's a great point. Take home point from this discussion is what is this doing long term? Are we creating bladder cripples? Probably in a few patients we probably are. Is that going to lean people toward cystectomy? So great points and certainly things that we'll see over the next couple of years for sure.

Great discussion, as I mentioned, Vig. Anything we haven't hit on that you want to mention any take-home messages for our listeners?

Vignesh Packiam: Yeah, I think, again, it's a really good time to be in bladder cancer because we're getting so many more treatments for our patients. I think it's really on us to know all of these details, because every patient is going to hear a little bit of a different thing that sounds interesting to them about each different treatment. So we have to counsel patients properly about what's going to be best for them.

Zachary Klaassen: Yeah, absolutely. Thanks so much for taking time out of your busy day to educate us on UroToday.

Vignesh Packiam: Thank you.