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Siamak Daneshmand: Hi, everyone. I'm Sia Daneshmand. I'm Director of Urologic Oncology at USC and I'm joined today by my good friend and colleague, Dr. Trinity Bivalacqua, Professor of Urology at the University of Pennsylvania. He doesn't need much of an introduction. He's an absolute expert in bladder cancer, a major thought leader, and I always enjoy talking to him and having him on any discussion. He's very thoughtful about the landscape of bladder cancer. Trinity, welcome. It's great to have you here this morning.

Trinity Bivalacqua: Thanks. It's my pleasure to be here. Appreciate it.

Siamak Daneshmand: Absolutely. We wanted to talk a little bit about the landscape. There's a lot of exciting things happening in both non-muscle invasive bladder cancer as well as metastatic bladder cancer, the recent ESMO presentations. But this morning I just want to focus on some of the new developments in non-muscle invasive bladder cancer, some of the new FDA-approved therapies, and sort of what's out there in the landscape, so to speak. I'll let you get started. Tell me about a brief history, where we've been, where we are now, and where you think we're going with non-muscle invasive bladder cancer?

Trinity Bivalacqua: Yeah, thanks. As you said right now, there's so much activity in this field in all aspects of the field, early-stage, muscle invasive, as well as metastatic. But I think one of the things that's the most exciting about non-muscle invasive bladder cancer is the new approval, and potentially even the upcoming approval, of different agents that we can use in our patients that meet the definition of BCG unresponsive bladder cancer. These are patients that have high-risk non-muscle invasive bladder cancer that receive adequate BCG, and unfortunately that has failed and they developed recurrent disease.

Currently, as you stated, there's sort of a history in this disease space where VALSTAR, which is a form of chemotherapy, was approved many years ago in the '90s. And as we unfortunately know, that's not very effective in treating recurrent disease. And then there was the investigation of systemic agents as well as intravesical agents that have led to the approval of, really, two agents at this point for BCG unresponsive bladder cancer. The first is a checkpoint inhibitor, as you know, pembrolizumab, which has been approved for BCG unresponsive CIS, and more recently, the approval of intravesical nadofaragene, or we in the field are accustomed to hearing about ADSTILADRIN. We will be using this. I believe it will, probably, for most urologists, it's going to be the go-to intravesical agent for patients with BCG unresponsive bladder cancer with CIS in particular. Currently, we use a lot of salvage therapies that include chemotherapy, doublet chemotherapy. But now with the exciting approval of nadofaragene, I think that this is ultimately going to be what we move towards.

Siamak Daneshmand: Yeah, I think so. We're used to delivering medicine intravesically and you mentioned doublet chemotherapy. We're talking about gem-docetaxel. I don't know about you, I find many have trouble in the community particularly delivering this because it's not approved, they need to be at a cancer center. There are challenges which I did not anticipate when this was sort of being used more often. But I think ADSTILADRIN is going to be easier to use and more sort of familiar for the community, particularly.

This was approved by the FDA relatively recently. It's actually been quite some time, but it's recently became commercially available. But this is gene therapy, right? We call it the first approved gene therapy in bladder cancer. And I guess many don't exactly know what that means. What does it mean, gene therapy? This was based on the phase II trial that you were a part of. It was published in Lancet a number of years ago. So do you want to tell the audience what is meant by gene therapy?

Trinity Bivalacqua: Sure. I think I'll also echo your comments about double chemotherapy, gem-doce. I work in a very big health system and a lot of our smaller hospitals that are in the community in Pennsylvania, actually, our patients have to travel very far distance in order to come and get that. So I also see the same issues, not my part, but on the East Coast, not the West Coast. But as far nadofaragene or ADSTILADRIN, as you stated, it is our first gene therapy that has been approved. It's a form of gene transfer. And I think the thing that urologists know and we need to educate everybody is that this is also a form of immunotherapy. So this is also what we're accustomed to.

Siamak Daneshmand: Exactly.

Trinity Bivalacqua: Gene transfer, this is a form of adenovirus that delivers the gene interferon beta. So this is exactly what's released when we give BCG, for example. You get an increase in cytokines, and one of the main cytokines is interferon. The team that developed this at MD Anderson, Colin Dinney and colleagues, brought this through phase II/phase III trials, particularly as it relates to collaboration with the SUO CTC, and we were very lucky to show that there is a lot of activity with this form of adenoviral gene transfer of interferon.

Importantly, this is a replication-deficient adenovirus. So this is safe. This is not something that is going to become incorporated into the genome, and ultimately, it does get upregulated and this virus gets taken up in the bladder and then it releases the gene of which is interferon beta. Now, this is a multiple-pronged approach. So the goal is an upregulation of our increase in interferon signaling, which also brings a lot of trafficking in the microenvironment of the bladder, which brings in multiple immune cells, in particular T cells. So this has got a lot of ways that it help prevent development of new papillary tumors in CIS.

Siamak Daneshmand: Yeah, it's very neat, isn't it? It sort of makes a mini factory within the bladder of the cells themselves producing interferon and acting locally. What I find fascinating is that you give one dose and you're good for 3 months. We haven't seen that. We're used to these weekly installations for 6 weeks. Everything we do has to be 6 weeks. But this is just the one time. So tell me about the schedule a little bit within the trial.

Trinity Bivalacqua: Sure. What was found early on is that because this is a gene transfer, adenoviral gene transfer, you actually get increase in interferon levels roughly, for the peak, is around 3 to 4 days, and it can last upwards of 7 days with a decline around 10 days. So this sort of weekly amount is not necessary. And because it's incorporated and actually infects, essentially, the entire bladder and has this multi mechanism approach, we only have to give it every 3 months. So I got to tell you, as you know, because you were part of these as well, the patients love it. They come in once every 3 months, they get their treatment, we get to scope them in our normal pattern every 3 months, and it really is a very efficient way of treating BCG unresponsive CIS, with or without papillary disease.

Siamak Daneshmand: So we've got a really cool mechanism here. It's a brand new sort of mechanism of treatment for non-muscle invasive bladder cancer. But does it work? Tell me about the results.

Trinity Bivalacqua: Yeah. Well, listen, it was FDA approved, and in reality, yes. It does work. If you look at the response rates or CR rates for patients that had CIS plus or minus papillary disease, the CR rate at 3 months was 53%, so half of the patients were disease-free, and at 12 months, 24%, or 1 out of 4 patients, were disease-free, which, right now, that is the best efficacy data we have for patients that have recurrent high-risk, non-muscle invasive bladder cancer that are unresponsive to BCG. If you look at patients with papillary disease, you see an even more remarkable response rate. At 3 months, patients that had papillary disease, 3 out of 4, 72% were disease-free, and at 12 months, 43%, so essentially 1 out of 2. So yes, this has activity, and because of the ease of delivery and the schedule, that's why I'll go back to one of my first statements, I think that's probably why it's going to be the go-to in this disease state.

Siamak Daneshmand: And one of the fascinating things, I think, when you look at those recurrence curves, there seems to be a flattening of the curve around 1 to 2 years. We don't see that very often either. We see sort of this continued recurrence rate. So maybe this has a lasting effect in the bladder. We don't expect it to last 5 years plus, but certainly I'm intrigued. And I think there's new data coming out that there is sustained sort of response at 2 years as well, and of course we'll have more and more data coming soon. The other thing, everyone wants to know, okay, this is gene therapy. It's novel, it works, but is it safe? Is it well tolerated? The side effects, what does this look like?

Trinity Bivalacqua: Yeah, I think one of the things that I found that was the ease of administration and the fact that patients actually tolerated it. One of the things that we didn't talk about, but I'll bring it up briefly here because I think it's important, in order for any form of gene transfer, adenoviral, adeno-associated viral transfer, you have to have a detergent or a way to disrupt the bladder lining, that gag layer in order to get the viral transfection. So with that, that's part of this. It's actually part of the actual gene transfer approach. So it's actually adenoviral gene transfer of Syn3 with interferon, and that Syn3 is really what helps disrupt the bladder urothelial lining.

When that happens, I can tell you most patients, when I say most, I mean the overwhelming majority of people, really don't have a significant irritation or problems with it. It's very well tolerated. If you actually look at the paper, the pivotal trial, the phase III trial, it was about 60%+ of patients had some form of grade 1 to 2 side effects, and the majority of those were people with dysuria, irritative symptoms. But I found, at least in my patients in the trial, that treating them with the anticholinergic, doing things both beforehand as well as within 24 to 36 hours, it didn't prevent us from actually treating them. Actually, I had a couple of patients that stayed on it for 3 years and it was just really well tolerated. So I don't think it's going to be a problem in clinical practice.

Siamak Daneshmand: Yeah, we did too. We were part of the trial as well here at USC, and same. We had patients who tolerated this extremely well, and were on it for extended periods of time for several years and are disease free. So I think, yeah, you look at those AEs, we basically don't have any serious AEs and very few patients came off trial because of AEs. So I think the combination of a well-tolerated agent once every 3 months with very few side effects is going to be a very attractive option for us in multiple different scenarios, where patients are either not candidates for clinical trials or they've gone through the various previous treatment options.

We got to the efficacy, we know it's safe, the AEs, so what's next? Recently, it made it into the NCCN guidelines. I see it's included in the 2023 NCCN update as an option for BCG refractory or unresponsive disease.

Trinity Bivalacqua: Yeah, I think we that are involved in clinical trials are going to start, probably, looking and saying, "Okay, I've got an FDA-approved agent which has actually pretty good efficacy and it's very well tolerated." I think people are going to start using this and we going start having clinical trials, which are going to include patients that are BCG unresponsive, also unresponsive to, for example, ADSTILADRIN or nadofaragene. There is a lot of questions that we're going to have to start asking ourselves, and we're going to have to start designing new trials to see how to sequence our treatment. That's really where the field's moving. Sequencing seen, combining intravesical agents.

Siamak Daneshmand: Combinations, yeah.

Trinity Bivalacqua: There's novel delivery systems that are now being sought out in the bladder for both chemotherapy as well as immunotherapy. So as we said earlier, this field is just really, frankly, exploding right now.

Siamak Daneshmand: Yeah, it's exciting. Exciting times right now for us who've been in this area for a long time, but we haven't had anything. Lastly, I just want to touch upon, people are asking already if patients are coming in, is this available? It's been FDA approved for some time now, but they want to know can we start using it? There's an early experience program that started in a few institutions around the country. We're actually part of that program, and it's slowly sort of permeating throughout the various centers, but it is available in select centers. We can start using it. It's fairly simple and straightforward, so we look forward to it. Again, you and I have had experience with it before, so it's going to be easy for us to go right back to it now that it's commercially available. I really look forward to having one more drug available in this space and being able to treat our patients.

Well, I want to stop there, Trinity. I really want to thank you so much for sharing your time with us this morning. It's been a pleasure. I look forward to seeing you soon at the SUO.

Trinity Bivalacqua: Yeah, absolutely. Thanks, Sia. Always looking dapper, you're the man.

Siamak Daneshmand: Thanks. All right, see you, Trinity.

Trinity Bivalacqua: Bye.

Siamak Daneshmand: Bye.