Siamak Daneshmand: Always a pleasure to talk to you and then be on this forum to talk about something that happens every day. This is a changing discussion with a patient. So what I want to do is just give a background for the audience of what we're dealing with here, what the treatment options are for patients. So I don't want this to be a full lecture, but just an overview. These are the updated NCCN treatment guidelines for BCG-unresponsive non-muscle-invasive bladder cancer, CIS with or without papillary disease, and then Ta/T1 papillary only without CIS. So we always start the discussion with the preference and the gold standard, so to speak, is radical cystectomy and, of course, enrollment into ongoing clinical trials. The other recommended treatment options are gemcitabine with docetaxel. That's been around for a while. We'll talk about that a little bit. The new gem intravesical systems at iDRS, the intravesical drug-releasing system, nadofaragene firadenovec, which has been around for a while, nogapendekin inbakicept, and then the other novel therapies.
But for NCCN guidelines, these are the current guideline recommendations. And you can see that for papillary disease without CIS, it's almost the same thing, but the category is a little bit different. Now on the systemic side, we also have pembrolizumab, which has also been approved in this setting for quite some time. So just very briefly going through these, obviously the nadofaragene and the IL-15 superagonist Anktiva, it's intravesical. The gem-iDRS is a device. It's a drug-releasing system, so that's placed also in the bladder. And we have some others under investigation as well, the CG0070 and detalimogene voraplasmid under investigation. So we just want to concentrate on today's discussion on the FDA-approved agents and how we go about making recommendations for patients, because it is getting complicated. I do like this slide. It seems busy, but I think risk categorization, as you have stressed many times in your lectures and panel discussions, is putting patients into risk categories is important.
I like the EAU guidelines because it does have these very high-risk features, and those are things we use in everyday conversations when patients have lymphovascular invasion, prostatic urethral involvement, or variant or divergent histologies, that's going to make us think very differently about a patient with high-grade T1, for instance, with these features. And for those I recommend, and I suspect you do, radical cystectomy if the patient is a candidate for it. And the reason for that is there's a high chance of upstaging at cystectomy. No matter how good a TURBT you've done, in a re-TURBT, there's not only a chance for progression later, but also at the time of cystectomy, chances of invasive disease and/or lymph node-positive disease. In some series, up to 15% of patients with high-grade T1 with high-risk features have lymph node involvement at the time. So you don't want to be treating these patients with intravesical therapy, and that's going to be ineffective.
So again, this risk categorization, for the most part, we're talking about high-risk patients. These are patients who are BCG-unresponsive or BCG-exposed, if you will. So start out with this always with a discussion, and this is exactly... I tried to order the slides and the discussion exactly how I do it in clinic. It is getting a little bit longer and longer a discussion each time with the patients, but this is where we start out with. Sequential gemcitabine and docetaxel, it's been around for a long time. We all use it. We actually don't have prospective data, and we all reference this great paper, which is a multi-institutional retrospective look at patients with CIS with or without papillary disease or just papillary disease. And you can see the two-year recurrence-free survival I tell the patients is about 50%, which is pretty good. And I think most of us have the same experience with gem doce.
It's fairly well tolerated. Obviously it's now the subject of de novo treatment in BCG-naive patients and the BRIDGE trial, and we'll see what that shows. But specifically in BCG-unresponsive disease, then this is one of the easy ones. Now, I say easy, but docetaxel sometimes is not available to many in the community, and so this can be a challenge and certainly internationally it's not as available as it is to us. Immunotherapy for BCG-unresponsive disease, pembrolizumab was approved in January 2020. It's been around for a long time, but when you look at the... And everybody knows Keytruda from multiple other indications, the [inaudible 00:05:52] quite good.
But in essence, if you look, this is of the responders, this is duration of response, which it is reasonable. But if you look at the total number of responders who are still responding after 24 months, the number is pretty low. It's less than 10%. Nine patients remained in CR after 24 months. And it then carries the potential for systemic side effects. So it's not usually our first go-to, but it's certainly something that should be considered if you've exhausted all other options and you're left with having a therapy option. The other FDA-approved agents, like we talked about, was the viral gene transfer with nadofaragene firadenovec, otherwise known as Adstiladrin, that was approved in December of '22, the IL-15 superagonist, nogapendekin inbakicept or Anktiva, that's given with BCG, in combination with BCG, that was April 2024. And then most recently, the intravesical drug-releasing system, gem-iDRS, that was just recently approved in September 2025, and that was the subject of multiple trials, the SUNRISE trials.
So we do have all these. And of course, we now have long-term results for Adstiladrin, the nadofaragene firadenovec, showing that the responses are fairly modest at one year, about 25% of patients are responding at one year. And then as you go further out to three years, not as many responders, you can see there's a degradation of response, as you can imagine, with most of these agents, but this has five-year results. But the good news is that not a lot of patients had progressed during this time. The cystectomy-free survival was 50%, so patients who are going on to other therapies, and the three-year overall survival rate was 90%. Now, this trial was done a number of years ago and reinduction was not allowed. And so there are modern trials now looking at combination therapy with Adstiladrin. And there's a trial called ABLE-22 that is examining whether addition of gemcitabine-docetaxel to Adstiladrin will improve outcomes in the setting.
But this is very much in our armamentarium, and I'll talk a little bit about when we potentially choose this. This is the IL-15 superagonist, again, Anktiva. I'll just show you the 36-month, again, cystectomy-free rates are quite high. CR rates at any time are good at 71%, and it's maintained at about 50% with long-term follow-up, which is nice to see. So now we're getting prospective data out to several years that is showing continued response. So that's certainly a great option for patients. And of course, gem-iDRS, we've seen this slide many times. This is a great cartoon depicting how the device is placed. It's a special catheter. And then the device is released into the bladder, has little gemcitabine tablets in there that are slowly released giving sustained release of gem into the bladder, and the results are quite good. The CR, the complete response rate at any time was 82% in these patients, many of whom are responding at one year. And we're awaiting long-term results on this. As you can see in the swimmer plots, there are a lot of patients who were early when this was reported and published.
So I just put together a table. Now you have to understand these are, as you, I think, mention all the time as well, these are all phase two single-arm trials. So we're not supposed to be comparing, but I just wanted to put it all in one place. This is certainly not a comparison. These are phase two again, single-agent comparisons, but it does give you an idea that we're doing better than the valrubicin days, for instance, when your CR rate at one year was about 10%. Now we're looking into the 40, 50% range, which is really encouraging to see. So I think these numbers are very close to one another. It's really hard to say what works better than another. The only longer-term results we have so far, as far as I know, is for nadofaragene, the five-year results like I just showed you, and for pembrolizumab, the two and three-year results.
So, okay. here and discuss... So this is what I in a nutshell in lay language go over with the patients, and then they're fully confused and at the end ask, "Well, what would you do?" So part of it is, a lot of it is the patient selection, obviously. There's so many considerations, there's socioeconomic considerations. There's a consideration of the practice when people ask me, I'm like, "Well, do you have this?" I just literally texted somebody yesterday. The patient said, "Can I go back to my referring doctor and get this treatment?" And I said, "Sure, let me ask him if it's available." And he said, "Well, I can't do it in this center, but I have to do it in this other center," and so on and so forth. So there are some economic and purchasing drugs or expensive drugs and some smaller practices may not be able to accommodate these extra costs as they have to buy and bill and things like that. So the economics of these things is beyond the scope of this discussion, so that's one consideration.
The second is the bladder itself. How does the bladder look in terms of capacity, in terms of being able to tolerate intravesical treatments, the volume of treatment? Nadofaragene is very convenient. It's a one-time installation. That's another one, can the patient come back even though our on year results may not be as high as the others? It is an extremely convenient dosing with once every three months, quarterly dosing for nadofaragene. I had a lady yesterday who I had been treating for a year and a half with nado. She was super happy, tolerating it extremely well, and had been disease-free for that time period. Nogapendekin is given with BCG. So there's been a little bit of a challenge recently with our BCG shortage because it has to be given with BCG. [inaudible 00:12:26] a little bit with the availability of recombinant BCG.
And so we now are using more of Anktiva just because the recombinant BCG, which is offered by the same company, is available to us. So that's also encouraging. So in a nutshell, it's just a discussion. And Inlexzo, it's an every-three-week insertion-and-removal process for the first 24 weeks, and then quarterly after. Some patients like that idea of something inside their bladder working in a sustained-release type of system. And, for the most part, respond quite well. So bladder volume, how the bladder looks, discussion with the patient. And if at the end of the day, and of course, we always talk about cystectomy as being the gold standard, I can only count on one hand how many patients said, "Okay, let's just go straight to cystectomy." I think most patients are very, very motivated to preserve their bladder.
So it can get confusing. At the end of the day, if the patient says, "I have no idea, you choose." We literally try to make the best decision for the patient and say, "Okay, well..." And it has to do with logistics as well to some degree. We did have time for this or we don't have time for that, then let's pick one of the other agents that's a little bit more streamlined into our practice.
Ashish Kamat: Thanks so much, Sia. I mean, again, chatting with you is always so much fun because it's a great discussion we have. And to be honest with you, your presentation was so perfect. It's almost like you anticipated questions I was going to ask you. Have we chatted before?
Siamak Daneshmand: Yeah.
Ashish Kamat: No, just kidding. But I really like the way you go about this, because I think it's a great problem that we have now that we have multiple choices. And you and I might be a little spoiled sitting in our ivory towers where we have access to all these drugs, but patients don't have access to be able to come and see you and me the way we might want them to. Some patients can't come once a week. Some patients can come once every three weeks. Some can only come once every three months because their grandson or granddaughter has to take time off.
And these are real practical considerations that go into our discussion. I also like the way you prefaced it because some people lose sight of the fact that in today's day and age, 2026, if a non-muscle-invasive bladder cancer patient ends up with metastatic disease, I think that's our fault. We should not allow the patient to get treated ad nauseum with A, B, C, D until they metastasize. That just doesn't make sense. But let me put you on the spot now, because again, let's assume I have BCG-unresponsive CIS with, say, TA disease. I'll leave alone T1. Let's not talk about the very high risk. And I say, "Sia, I have everything at disposal on my hand. My bladder's in perfect condition. I run marathons. I want something that will give me the best result." Which one would you recommend for me?
Siamak Daneshmand: Yeah, you really put me on the spot because I think that's a tough question to answer which one has the best result because it depends on how you think of the best response. So again, these are phase two. It's hard to compare them, and we have complete response at any time, but what we wanted is durability of response, and the data's still coming in terms of durability. So honestly, it's a really tough question to answer. I think for a practical purpose-
Ashish Kamat: I'm not going to ask you easy questions. I'm not going to ask you easy questions. Doctor, you got to tell me, what are you going to recommend for me? I flew all the way from Timbuktu to see you. Come on.
Siamak Daneshmand: Well, there was a study by Ashish Kamat saying more BCG might help. So yeah, I think for practical purposes, gemcitabine docetaxel is our default so to speak, if we're not doing a clinical trial. And I say that because I don't think it burns any bridges. I think it's highly accessible, at least to us, and the results are quite good. Again, we don't have prospective data, but pretty good retrospective, and very, very good inter-observer, meaning all of us when we talk to each other, we seem to have similar data at our own institutions and we believe that 50% number two years. So I think for the patients, and then we're not burning any bridges, we can certainly go to another treatment option after that.
Ashish Kamat: And when we talk to our community colleagues though, they say that gemcitabine docetaxel is actually very difficult for them because, A, they lose money not just on the drug because, like us, they're not in academic places. So they lose money on the drug, then they lose money on the space that they have to save for the patient. So gem doce really I don't think is going to catch on in the community, period. I think in the community we have to, in some ways, resign ourselves to the fact that if it's not got the payer behind it, the patients are not going to get it. And I like the way you say that we have to think about patients getting treatment in their own facility. When you're advising folks that are asking you, "Hey, Dr. Daneshmand, can I get treatment in my own community?" And let's assume the community practice has multiple different agents available. Are you trying to steer them to one or the other just based on that factor?
Siamak Daneshmand: [inaudible 00:17:57] one versus the other. But yesterday I had this conversation with a patient who had failed gem doce right before Adstiladrin, and we had gone actually quite some time with Adstiladrin for over a year disease-free, and now we developed recurrent disease, fully resected. It was high-grade T1 actually, but an 82-year-old woman absolutely will not have a cystectomy. So we had a discussion and I said, "Well, we could certainly do Inlexzo, but having failed gem doce, we're not quite sure we don't have the data for additional gem." It might be different because it's sustained release. But to me, the next logical step was Anktiva. And so I called the practice and I said, "Do you have Anktiva available?" And they said, "Yes, we have to have it at this other center." And I said, "As you know, it has to be given with BCG."
So there are those practical considerations. And I thought for her, Anktiva would be the next best step, but started planting the seed that if this doesn't work, we've failed multiple lines of therapy, and make sure we do cross-sectional imaging, that we're not missing something outside the bladder, any lymph nodes that may be developing. So I think people forget that as they move from one therapy to another, that we should be doing cross-sectional imaging on these patients, which is done in the trials, but not so much in clinical practice.
Ashish Kamat: And then last thing, Sia, I mean, again, congratulations on all your leadership positions in multiple organizations. What is your sense? And I'm going to put you not on the spot because I know you and I think about this similarly, but what's your sense as to how long can we keep going on with these single-arm studies? Because as you've showed on your slide, yes, we can put numbers up, but it really doesn't help us when we don't have a comparator arm. And now we have all these agents approved. Do you think as a society, as a group, we should go on and now have controlled studies?
Siamak Daneshmand: Yeah, absolutely. So the next phase is we now are, I think, done with these single-arm phase two studies showing efficacy of these drugs, which was an important step the last few years. And as you're heavily involved in the FDA discussion and things like that, the next step is really comparative studies. We need to sequence these drugs. We need to have comparators so that we can say, "Okay, this is first line, this is second line, this is third line," so on and so forth. There are some trials coming forth that are doing exactly that. It's going to take some number of years, but this is how I see the next five years going, companies and trials trying to position themselves in specific places as in second-line therapy. There's already one trial looking at one agent specifically in a third-line setting post BCG, post-one other treatment. So that's going to be interesting.
This is the first trial I've seen that's trying to position themselves in third line, second line, I guess second line post BCG. But yeah, sequencing is the next big thing. Unfortunately, all the scientific endeavors trying to predict response to one or the other based on so many other factors on a cellular and a molecular level really have not given us any clues as to who's best for what treatment. There's no receptors, there's no molecular markers or anything. Having said that, I think FGFR3 story for intermediate risk disease is completely different, but we don't really so far have that for... We have some predictors of response, but they're not really robust, and we're still back to knowing what we know clinically from the patients. So I'm hoping more studies will shed light on who may be a better candidate for intravesical chemotherapy, for instance, as opposed to an immune response related type of treatment. So those trials are underway, but like you mentioned, comparative studies are the next big step in this space.
Ashish Kamat: Sia, always incredibly fun chatting with you. Thank you so much for taking the time.
Siamak Daneshmand: Thanks, Ashish. Thanks so much.