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Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center, and it's a distinct pleasure to have once again on this forum someone who really needs no introduction, someone who's truly an expert in urologic oncology, bladder cancer, professor Stephen Boorjian, who is currently the chair of the Department of Urology at the Mayo Clinic and has led this very important trial in the urologic oncology field, which essentially led to the approval of the first intravesical therapy for BCG-unresponsive disease, in truly what is the new paradigm that has been adopted by the field to study these agents. Dr. Boorjian has taken the time off today to come and spend with us and go over some of the nuances and updated results of the trial. So Stephen, thanks for taking the time, and the stage is yours.

Stephen Boorjian: Well, Ashish, thanks very much for having me here. It's been an honor to work together, and happy to be able to share a little bit of background and some data on our trial here. So the agent that has been developed largely in reflecting the work of Dr. Colin Dinney at MD Anderson is rAd-IFNα, which is a replication-deficient adenoviral vector, and it is linked to Syn 3, which essentially functions as a detergent to allow transduction of the agent once it's placed into the bladder across the cell membrane and into bladder cells. And fundamentally, what this drug does is turn the bladder into an interferon bioreactor, making high levels of sustained intravesical interferon protein. We studied this in a phase three single-arm trial that represents a unique collaboration between industry, the FKD company, and academics with the SUO CTC organization. It was really that partnership that brought together a number of different centers to allow this trial to be conducted.

It was also done with significant input and guidance by the FDA. This was, as you talked about, sort of one of the paradigm introducing trials of a single-arm phase three or registration clinical trial. And it was testing nadofaragene firadenovec intravesical interferon therapy for patients with BCG-unresponsive non-muscle-invasive bladder cancer. The primary endpoint of the trial was really to study the efficacy in patients with BCG-unresponsive carcinoma in situ, and there were 103 patients in the efficacy population. And what the trial's primary finding was, was that the complete response rate among patients with BCG-unresponsive CIS was 53%. Interestingly, all complete responses were noted within the first three months of treatment, and this was the publication that we put out now two years ago in Lancet Oncology. Some very important secondary endpoints with the trial also evaluated, was the efficacy in patients with BCG-unresponsive papillary non-muscle invasive disease.

So TA and T1, there were 48 patients in the efficacy cohort here, and the endpoint of high-grade recurrence-free survival was achieved at three months, and 73% of patients for an overall three-month high-grade recurrence-free, or CR of 60%. We also had 12-month data on these patients that can be seen on the slides here. So when the patients with carcinoma in situ two from the overall cohort 12 month CR rate was 24%, papillary disease 44%, and again for the overall cohort of 31%. In this population of patients with BCG-unresponsive disease, as we understand, many are elderly, many have other comorbidities, and they are going to be either unable or unwilling to undergo radical cystectomy, which for several decades has really been all we've had to offer these patients. So an important endpoint in the trial was to look at cystectomy-free survival, and we found that by 12 months, 25% of patients approximately had undergone cystectomy.

So the estimated two-year cystectomy-free survival was 65%. I think that really speaks to the ability of this treatment to be able to avoid cystectomy in a substantial cohort of patients. Very important when we're evaluating new agents is to look at safety. We looked at safety from a number of different perspectives. One area, we looked at safety was with disease progression, making sure that patients were not experiencing disease progression. We found that the progression risk during treatment was 5% to muscle-invasive bladder cancer. We also looked at safety from the standpoint of adverse events and as we might expect from an intravesical agent, the most common adverse events related to treatment with nadofaragene were irritated lower urinary tract symptoms. And the vast majority of these were Grade 1 or Grade 2 events. There were three patients who discontinued treatment due to treatment-emergent adverse events.

There were three patients who had what would be considered serious AEs, and there were no deaths due to treatment-related adverse events. So overall, the treatment was fairly well tolerated. And in parallel to that, we believe that it represents a significant advance for patients because of its treatment delivery schedule. This treatment is given intravesically once every three months, which is favorable both from a patient standpoint and from a clinical practice standpoint. Now, as we just had the opportunity to present at the winter SUO, Society of Urologic Oncology meeting, we have the 36-month follow-up data, and as we've seen with other immune-based therapies, there's a cohort of those patients who achieve a complete response that are able to maintain that complete response. And here what we found was that 25% of patients who had achieved an initial complete response maintained that at three years. When we looked at the overall cohort of patients with BCG-unresponsive CIS, that 103 patient cohort, we found that 14% remained high-grade recurrence-free, that 54% remained cystectomy-free, and that the overall survival was 90%.

We're in the process now of putting together the five-year data and are excited to have the opportunity at this coming AUA spring annual meeting to present it there. So let me stop at this point and see what questions we can work through together and perspectives we can add to the trial data.

Ashish Kamat: Thank you so much, Stephen. I mean, that was a very nice succinct summary of all the work that's been done in the results. As newer agents have come up, people often look at the results from this trial, which, as you mentioned, was a collaborative effort and took a lot of initial thinking about the trial design, the outcomes, the endpoints. So people look at these results and then compare and contrast them to currently reporting trials that have learned from this. And of course, the KEYNOTE-057 study, could you help our audience sort of understand why the results that we see in this trial are actually going to be reflective? At least we think of what we see in our patient population, and it's not cherry-picking. I mean, this is what the kind of patients we see. Could you help our audience understand that a little bit?

Stephen Boorjian: Yeah, I mean, I do think, to your point, these patients in this trial reflected real-world BCG-unresponsive patients. They were a heavily pre-treated cohort. We used the fairly rigorous definition of BCG-unresponsive disease almost to ensure that these patients did meet a criteria of having been heavily pretreated. But as a reflection of that, we saw that these were patients who had received multiple courses of BCG, they were an elderly cohort of patients, they had comorbidities. So I think in one aspect that is very important because the patients that we see with BCG-unresponsive non-muscle invasive bladder cancer are often an elderly cohort of patients who have other existing comorbidities and competing risks of mortality where we are looking for alternatives. And very importantly, they are looking for alternatives to radical cystectomy. So you mentioned, for example, the KEYNOTE trial that looked at pembrolizumab.

The concern about immune-related IV checkpoint inhibitor therapies is that they do carry a risk of immune-related toxicities, the Itis's, so to speak. And in an already baseline elderly patient cohort with existing comorbidities, the subsequent incremental impact on those patients can be not insignificant. I think the other issue with that specific therapy is the treatment delivery. So it's an IV medication that, at that trial, was given once every three weeks for two years. Now there's a six-week formulation. So it's a burden of therapy on patients, and it does carry with it the toxicity risks, which in this patient cohort are really, really important to be thinking about.

Ashish Kamat: Yeah, and again, you mentioned the dosing schedule, right? Once every three months. It's good for our patients who sometimes don't have access to healthcare and they have to drive a distance, they have to come through weather-related issues, hurricanes in Houston, snowstorms where you are, and they have to get there. So if they get there once every three months and it works for them, it's a great opportunity for them to spare their bladder. And if it doesn't work, we find out pretty early on. So it's not like it's a futile, repeated treatment. But that brings me to a question which I often get asked and I'd like for you to shed some light on, is what about re-treatment? In ongoing studies that are reporting, re-treatment is allowed, in this study, re-treatment was not allowed if you had a recurrence. What's your sense as to how that'll be?

Stephen Boorjian: Yeah, so the really important question. Absolutely. So re-treatment in this trial was not allowed if you had high-grade disease. So you could essentially be treated with maintenance if you demonstrated a response. But as you've pointed out and as you've shown in work that you've done, there's a substantial proportion of patients, especially when they're being treated with immune-type-related intravesical therapies, that will respond to essentially a re-challenge. And this is an area that is under consideration for future trial development with this medication, which is can we be using this in patients as a second challenge in those who don't initially respond? So I think the short answer is, right now we don't know. I think there's enough compelling data with other treatments that a re-challenge with this would be warranted, especially because what we have seen in terms of disease progression here is about 5% to 12 months. So I don't think we would lose a safety window if we were to see a patient who had CIS again, for example, or even high-grade TA, and offer them a re-challenge with the treatment.

So I'm excited to see prospective evaluation of repeat dosing in patients who've had one initial dose and have high-grade non-muscle-invasive disease go forth. And I think we'll have to see whether this is able to be comparable to the other therapies that have shown that cohort of patients who does respond to a second challenge.

Ashish Kamat: Yeah, I think one of the things we've learned from this study and even the other ongoing studies is that there is a window where we can safely retreat patients, but that window is not forever, and we have to be prudent about how often we retreat and how long we let the disease progress. The other thing that you mentioned as to where this fits into the paradigm, right? The unmet need for our patients, it's great for our patients, right? It's great for us, but it's even better for our patients that they now have options. They have the option of pembrolizumab, the option of nadofaragene, and clearly each one has its risk and benefits. We, actually, the International Bladder Cancer Group, had a retreat in August, a full one-day retreat, to try to figure out where these different approved drugs would fit in into the treatment paradigm. Let's assume you have five different approved drugs. And not to put you on the spot, but I don't want to put you on the spot because I know you've done a lot of thinking on this.

Where do you think nadofaragene, assuming we have five different approved drugs, right? Which type of patient? Which scenario would you say, "This is where I would think of this drug first above everything else?"

Stephen Boorjian: Yeah. I-

Ashish Kamat: Let's bring in Gem/Doce too for the discussion.

Stephen Boorjian: Of course. So I would say that this would be a very good first-line, BCG-unresponsive treatment, particularly in patients with significant other comorbidities. And those patients who may have, as you just mentioned, access issues. It's something that I've gained an appreciation of just practicing now for a number of years at Mayo Clinic in terms of where people can get healthcare, where people can get specialized care. So for a patient in whom having an immune potential systemic hit would be particularly worrisome, I think this is a great option. I think it's a great option in patients who live a great distance from care, or a distance where that's going to have the sort of traditional six treatments intravesically once a week plus a maintenance schedule, is going to be burdensome on them or their caregivers. So that's a nice fit, where I think this would work well.

Then I think what's going to be interesting to see is, which we don't yet really have great data on, is the sequence, meaning can it be used well in patients who have had a checkpoint inhibitor therapy and have disease recurrence? And I think, as to your point, the number of different options increases sequencing, and understanding the potential impact of prior therapies on subsequent therapies is going to be really important to know. Do we know if this has better, worse, same efficacy in somebody who's had a checkpoint inhibitor in the past, or as these newer agents that are sort of been granted breakthrough designation go through, get approved, or don't, what is the impact of prior intravesical therapies with some of those treatments on this one? But I would say right now, very good first-line option, particularly in patients with significant comorbidities or difficulties with access to care.

Ashish Kamat: Great point, Stephen. Again, in the interest of time, let's wrap it up. We could chat on this forever, obviously, but thank you once again for taking the time and spending with us and the UroToday folks. Thank you for allowing us to do this.

Stephen Boorjian: Sure. Thanks for including me. It's been fun to be here, and an honor to be invited back.