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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urology and Cancer Research at MD Anderson Cancer Center. I am welcomed today by Dr. Angie Smith, who is an Associate Professor at the University of North Carolina and the Director of Urologic Oncology.

Dr. Smith is going to talk to us today about the natural history of high-risk non-muscle-invasive bladder cancer and then have a discussion on novel therapies versus cystectomy, both from the standpoint of efficacy as well as actual patient choices. Angie, I'm looking forward to your presentation and our discussion, and I'm going to hand over the stage to you.

Angela Smith: Thanks, Ashish, and thank you for inviting me to talk about this. This is, as you are well aware, it's a challenging space, but it is also an exciting space because so many new treatments are coming down the line. I'm going to talk a little bit about the natural history of high-risk disease, and then talk a little bit about patient choices that need to be made when non-muscle-invasive bladder cancer, in particular, returns after BCG treatments.

My disclosures are here as they relate to grant funding. PCORI, BCANTT funding, Genentech, and some institutional funds. Then I am also on the advisory board for a few different organizations as they relate to patient-reported outcomes.

So, very briefly, I'm going to just speak a little bit about natural history. I'm going to talk about decision-making as it relates to high-risk non-muscle invasive bladder cancer, and then I will pivot a little bit into novel therapies. I won't touch on all of them. We don't have time because there is so much going on in this space, but talk about a few of them and then considerations for future trial design. It'll be fun to discuss this a bit with you today.

So before I continue, I just want to ground ourselves on what I define and what we define as high-risk non-muscle-invasive bladder cancer. We always go back to the AUA risk stratification tables, and so if you're looking at a screen, it shows low risk, intermediate risk, high risk, and today I'm talking about high risk. And that is any recurrent high-grade TA, large high-grade TA, high-grade T1, any CIS.  But, in particular, I'm going to talk a little bit more about basically BCG unresponsive disease in high-risk non-muscle invasive bladder cancer because that is where a lot of the new trials are working in. Not to say that there isn't work being done in all these spaces, but I think specifically, in what we term BCG failure.

So starting out with the natural history of high-risk non-muscle-invasive bladder cancer, I think it's important to think a little bit about it because that is how we think about the risk groups and why the risk groups matter. There have been several studies that try to better understand the natural history of high-risk diseases. And I don't have it on the slide here, but we do have the very large EORTC combined analysis of around 2,500 patients that was used to create that nomogram that we are well aware of using. But that looks at predicting recurrence progression, but it looked at five-year risks of recurrence and progression. When we think about this disease, we actually have to think about it, even more, long-term because natural history is a long natural history.

And so I wanted to highlight this study. This was back in 1997, and this was done out of Memorial Sloan Kettering, but it was a study of 86 high-risk patients, and it was a randomized control trial of TUR alone versus BCG. It was a crossover design, but what that study allowed us to look at is a 15-year median follow-up. And what they found is the population that was high risk, 44% were high-grade T1, 81% had CIS, 53% progression, about a little over one-third ended up with a cystectomy. If you look at 10-year and 15-year disease-specific survival, it's 70% and 63% respectively.

I think that's important because when we reflect on the natural history of high-risk disease, it depends on our frame of mind. This is actually from you, Ashish, and I'm sure you remember it because it made a big splash in the Twitter sphere in which you posted a provocative tweet in which you basically equated the disease-specific survival of high-grade T1 with what would be equivalent to prostate cancer. That was clinical T3b, Gleason 10, 12 out of 12 possible positive cores, a PSA of 75.

When we think about that, I mean, think about how anyone listening, how we would counsel prostate cancer patients for that type of disease, and versus how we handle high-grade T1. I think that you and Jed Ferguson, who is now at UAB, did a nice little commentary about this, talking about distinction bias and contrast effect. I'm not going to belabor this, but it is just a sense that we do have cognitive biases, and that impacts the way in which we view high-risk non-invasive disease and it really actually impacts, even if we don't see it or realize, it impacts how we frame the type of disease and how we counsel our patients who are facing BCG refractory, BCG unresponsive non-muscle invasive disease. So I would ask ourselves, do we minimize the danger of high-risk disease, and would we do the same with another disease? I think it was a really provocative tweet, but it is one that I think should still be considered today in how we think about it.

Most recently there was a study that was published by Jim Catto's group. It's the BRAVO-Feasibility Study, and what I think is interesting about this study is a couple of things. One, this was a study that compared radical cystectomy against intravesical therapy for high-risk disease, but keeping in mind, this was not BCG refractory disease. In the US, that is in our mind, that is how we frame it because we don't tend to think about cystectomy unless they are very high risk or a young patient, and we call it early cystectomy, but these studies randomized or attempted to randomize these patients. I think what was interesting in terms of the findings was that one, quality of life was very similar between the two groups and so it challenges our belief that maybe cystectomy diminishes the quality of life. But I would just question, does it? It may be different in the patient's mind of not having a bladder, but there is a lot of side effects that they need to better understand if they seek intravesical therapy.

The other interesting thing I'll just briefly touch upon is that they had multiple sites in this study and they looked at screening logs and initially, the patients had not yet been approached by their provider, 1% had a treatment preference. But after that, there was a very high percent that had a treatment preference at that point. And I think that is important because that suggests that maybe there is some lack with equipoise, maybe it was a lack of enthusiasm, but I also think it might very well be the way that the treatment was portrayed across sites because essentially 47 out of 50 enrolled patients in this study were from one site. Everybody else had really struggled to recruit. You wonder about how these patients were counseled.

But I think in the end, the real question is, do we understand the trade-offs? Are we understanding how we are going to sequence all of these new therapies that are coming down the line? We don't really have sufficient data to adequately answer that question, I don't think yet. We have some data, but how do we really make sense of it all?

I like this infographic because it shows all of these salvage therapies for BCG unresponsive disease. We have checkpoint inhibitors, and we have targeted therapy and viral gene therapy, and others. So I will just touch on a few of them today, and we will have a discussion. But of course, pembrolizumab is relatively new. It is now FDA approved, but this was a novel concept of using pembrolizumab for BCG unresponsive, essentially carcinoma in situ. What they found was a 40% complete response rate at the first disease assessment, and then 46% of those experienced a 12-month duration of response, essentially 19% of all treated patients. Yes, there were some adverse events as you would expect with a checkpoint inhibitor, but it was fairly well tolerated so it certainly added to the armamentarium of what we have to treat. Based upon that, the FDA of course approved it. We have this now, and many of us are redefining the way that we treat patients in this space because where it was really largely driven by urologists, now we think about it in a multidisciplinary way because many medical oncologists are delivering this medication.

Another I just want to touch upon, and it is not yet FDA approved, but I think everybody hopes it will be soon, is nadofaragene. This was led by Steve Boorjian. This is essentially an adenovirus vector that the human interferon alpha-2b gene gets incorporated in the bladder lining allowing for an expression of a large amount of that protein. I think the other interesting thing I will point out about this is, it is intravesical delivery, but not as rigorous as we are accustomed to. It is actually delivered every three months rather than once a week for six weeks or traditional induction therapy.

And in any case, what they found was that it achieved a 53% complete response rate in patients with CIS, and the complete response rate was durable with 45% of those at one year demonstrating complete response at that point. It was well tolerated. It has an acceptable safety profile. I already talked about the favorable delivery schedule, but certainly a promising option.

The last thing I'll just touch upon is oportuzumab or vicinium, which also has a Phase 3 trial that is being reported. This is basically a recombinant fusion protein. It's comprised of an anti-EpCAM antibody linked to a variant of pseudomonas exotoxins. This is actually instilled in a way, it is a little more rigorous than we are accustomed to, so it's two hours, twice weekly for induction for six weeks, and then you have weekly maintenance for six weeks and then if you are disease-free at three months, you're going to have maintenance every two weeks for up to two years.

And in this trial, their primary endpoint, much like others, is a three-month complete response rate. It was about 40%. So it aligned with what we have seen in the durability response, and also aligned with nadofaragene and what we've seen with pembrolizumab. But I think that I just would draw attention to the serious adverse events, and they had a little bit more than what we are accustomed to. So you can see that in terms of this Phase 3 trial, there are about 22% with grade three to five adverse events. It's certainly not free of side effects, and we will have to also consider the delivery schedule.

But I think the big elephant in the room, and certainly, there are more trials that I haven't covered. We're trying to do this in a brief, little snapshot of the landscape. The big elephant in the room here is that these are all single-arm trials, and the FDA understandably recommended this based upon where we were with regard to the treatment of BCG refractory disease. But now we probably need to look in the future in how we might consider changing the design of some of these studies and looking more forward to comparative effectiveness research, where that compares the effectiveness of two or more interventions, examining the risks and benefits, in particular looking at specific patients and who might benefit most with certain treatments.

PCORI, the Patient-Centered Outcomes Research Institute is essentially one of the largest funders for patient-centered comparative effectiveness research, and their mission is to help patients make better-informed healthcare decisions by understanding the risks and benefits of treatments and evaluating their head to head.

I've had the pleasure of putting together a study with my research partner, Dr. John Gore, and we have 28 investigators, including Dr. Kamat here, across the country to address this important question through a pragmatic trial design that is actually, it is observational. This was all actually designed with patients in mind, designed with patients sitting at the table. The aim here is to compare patient-reported and patient-centered clinical outcomes between patients undergoing cystectomy versus bladder-sparing medical therapies. That includes pembrolizumab among patients who have non-muscle invasive bladder cancer that returns after BCG. And also to understand and characterize the heterogeneity of these treatments. Because we know we have a lot on our plates at this point.

We're enrolling 900 patients and a handful of support caregivers. We've very intentionally selected sites with diverse geographic locations and types of community practices and academic practices. We're following patients for up to four years. When we look at outcomes, we actually went to patients, and said, "How would you rank these outcomes and which other outcomes are important?" You'll see here, we are looking at survival, we are looking at the ability to retain the bladder, progression of the disease, but we are also looking at things like financial burden, and urinary quality of life, and some others as well.

This is the trial or at least the schema of this, and essentially it is pragmatic. So it's a broader inclusion criterion than what we are accustomed to with Phase 2 and Phase 3 clinical trials in this space. It was designed intentionally for that because that is how we practice. We do not have those very specific patients. It's actually sometimes hard to find them, to that very specific inclusion criteria. But the patient makes a choice, cystectomy versus bladder-sparing therapy, and then we follow outcomes at 12 months, and we are doing a variety of other evaluations looking at time trade-offs, understanding different types of health states, doing some qualitative phone interviews of patients, and caregivers.

And so, I'll end there. This is I think, an interesting space because it makes us think a little bit more about how we counsel our patients. Yes, we talk about progression and survival, but we also have to understand that in the context of meaningful patient-reported outcomes and how those all work together for specific types of patients. Now with several novel agents becoming available, we do have to think a little more forward about trial design and how we enable comparative effectiveness research to help our patients make well-informed treatment decisions.

So again, thank you for inviting me here, and I'm happy to have some discussion about this.

Ashish Kamat: Thanks so much, Angie. That was a very, very well put-together talk, and as usual, you covered a lot of important information in a nice succinct manner. You mentioned the different agents that are being reported out on, and obviously, pembrolizumab has been approved. The other agents are a little bit on hold right now for various reasons. How would you factor in, I guess the off-label in some ways, de facto standard in the US now, which is combination chemotherapy for our patients when you are counseling them on options other than radical cystectomy, which we will touch upon in the next question. But how do you approach approved versus not approved off-label agents?

Angela Smith: Yeah, that's such a great question because I mean, I think that's boots on the ground. That is what we all are doing every day. I use gemcitabine/docetaxel, but we don't have Level 1 evidence for its efficacy. We have retrospective evidence that suggests that it is helpful. And I know there are some individuals, and Max Kates is looking into the use of gemcitabine/docetaxel versus BCG to get better Level 1 evidence in this space, but until we have that, I talk to my patients about we do have some evidence, but it's not definitive. I tend to support clinical trials. And so I usually present them all. I think it's the patient's decision. And I think there are a lot of things that go into this.

Some of these patients, as you know, you are a referral center, some of these patients travel long distances and have certain challenges in terms of these types of logistical difficulties. So sometimes that goes into their thoughts because if they are going to try gemcitabine/docetaxel, I'll give you an example. That can be done locally with their local urologist who referred them to me, but if they are willing to travel and they are willing to consider a promising clinical trial, then I'm going to offer that here at UNC. But I think every patient is different. I think you do have to give a lay of the land, and it is hard to do that.

One thing is with CISTO, we have an advocate advisory board, a bunch of patients who help advise our study, and we have an external advisory board. These are clinician experts around the country. And what we realized is, you have the after-visit summary you share with the patient, and there's not a really good brochure, so to speak of sharing all the things you try to cram into that very brief discussion. Even if it's an hour, it is not enough time. I'm sure you agree. You just have to cover so much ground, and for each one, you're talking about benefits and risks and their personal preferences, and then the level of evidence and all of that. So we are actually creating a patient guide that BCAN is going to have on their website that providers like ourselves can actually put into the after-visit summary, maybe type some notes based upon the discussion, but at least have something to show that lay of the land of what we have because it's constantly changing and just hard to cover it.

Ashish Kamat: I agree. It's ironic about the Level 1 evidence when we talk about it because if you really think about it, based on the FDA guidance document, the registration studies that obviously got pembro approved and nadofaragene hopefully when FerGene comes back, they will move it forward and try to get it approved. And then, of course, oportumizumab. But those are not Level 1 evidence studies-

Angela Smith: True, true.

Ashish Kamat: Because they are not randomized-

Angela Smith: You're exactly right.

Ashish Kamat: So we kind of have to rely on what we have and use that for our patients, which again brings me to the CISTO Study, which I think is really going to provide us and our patients such important information that is really going to help us not only design trials but counsel patients and develop educational tools as you have mentioned. Could you, from your, like I guess, 30,000-foot point of view, as well as diving deep down into the weeds, share with our audience what you are expecting ... Again, not to predict what you're going to find from this study, but what are you hoping you are going to get that will actually really help us address this issue with our patients?

Angela Smith: I think from, really the big perspective is that if you think about a randomized controlled trial and true Level 1 evidence ... It's randomized and there are two, it's comparative effectiveness so you have two interventions. One of the drawbacks of those is that your inclusion criteria, the population that you enroll, are quite limited. We know that, and that's an issue with randomized controlled trials. But it's understandable also because in these rigorously designed trials you want to have something that you can compare. But the issue is that it's not the real world. Not everybody will be eligible for that trial and therefore it's not generalizable.

So what we're actually looking to find ... I can't tell you what we're going to find, but I think what we are hoping to see is that depending on certain types of patients, maybe patients who have a specific type of preference, we might say, "Hey, look, this is the outcomes you get among your type of patient, your age, your gender, your race ethnicity," any kind of characteristic of that patient.

I think that would be helpful because we know, I mean, PCORI's, I think their motto is finding the right treatment for the right patient at the right time. And sometimes it's hard to do that without a pragmatic design. So this design, hopefully, and we've designed it in a way where we will have diversity embedded within the trial. That way we can take a look and say, "Hey, based upon who you are, here is what happened among patients who look like you." And I think that is going to be extremely valuable because we know this patient population is very heterogeneous, very heterogeneous. I mean, we have young and healthy patients, we have older patients who, maybe a cure isn't their intent. Maybe they just want to maintain quality of life, and they are willing to sacrifice some percentage of survival points for example, for maintaining the specific quality of life they currently have. That's what I'm hoping to find. I don't know what we will find, but I suspect that there are going to be differences there when we really take a look.

Ashish Kamat: I'm really looking forward to the data that you're going to collect and what comes out of it. Because one of the things that we sometimes are faced with or wrestle with is all the molecular studies and subtyping and everything that we are doing clearly is trying to personalize therapy for the patient based on the tumor characteristics. Clearly, that is years away from being ready for prime time. But when it is available, it will be matching therapy to a patient's tumor. But what about the patient? What about what he or she wants? I mean, maybe they don't want what's best for their tumor, but they want what is best for them? Which might be different from any gene expression profiling. We can't really forget that, which is a very important point. I'm glad that CISTO is going to address that. Angie, let me give you the closing stage and have you share with our audience your closing thoughts on what you presented today?

Angela Smith: Yeah, well, so I think we know that high-risk non-muscle-invasive bladder cancer, particularly BCG unresponsive disease is a challenging space. But the reason for it is because we're having an increased number of novel agents that have efficacy, but we really don't know how to best apply them, how to sequence them, how to counsel our patients. And so in the future, what I see as the future of this space is getting a better handle on how we use these medications. Also, reflecting on how we counsel our patients and be sure that we don't embed our own cognitive biases about quality of life. Because we now have some pretty good data that suggests that quality of life, for example, for cystectomy really doesn't differ from some of these intravesical agents.

So again, just being very cognizant of how we present data to our patients, ensuring that they have all the necessary information, understanding their goals of care, and trying to wrap it all with a nice big bow for a personalized treatment plan for these patients. Hopefully, we have better answers in the next five, six years, but until then we can all do our part by just being thoughtful when we see each of our patients in the clinic.

Ashish Kamat: Thank you once again, Dr. Smith, for taking the time out of your busy schedule and sharing it with us today. I wish we could meet in person, but I think that's going to have to wait for some time. So until then stay safe and stay well,

Angela Smith: Thank you, Ashish. Thank you for inviting me.