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Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center. And we have Dr. Mark Tyson, a professor at Mayo Scottsdale. And Dr. Tyson obviously doesn't really need an introduction. Really one of the stars in bladder cancer and actually all of urologic oncology.

Dr. Tyson actually presented an important work in the P2 program in the AUA 2025 that focuses on practice changing and paradigm shifting work. And it was on looking at the BOND-003 cohort study focusing on actually treatment options for BCG-unresponsive disease.

So, Mark, first of all, thank you for being with us. And secondly, I think let's focus on the cohort C patients, the patients that had CIS that was unresponsive or had disease continuation following BCG. So again, let's hear about kind of the key points of that study.

Mark Tyson: Thank you, Dr. Chang. Thank you for having me. I'm delighted to be here.

Sam Chang: OK, we can't go any further without, OK, Sam. Good. All right.

Mark Tyson: As you said, it was presented in the practice changing, paradigm shifting plenary on Saturday at the AUA. And I do think this is a major-- represents a major shift in the practice. As you know, these patients really have not had many good options in the past.

In the last few years, we've seen some development. And so I do think that this BOND-003 trial, building on over a decade of translational research, it's kind of starting to come to light. And we're starting to see just exactly how valuable increased imaging could be for these patients.

So BOND-003 was a single arm, open label phase three registrational study that enrolled patients with BCG unresponsive CIS. So, BCG unresponsive patients meaning they've had adequate BCG and had a recurrence within 12 months of CIS. And of course--

Sam Chang: So adequate BCG, for those perhaps not as familiar, is an induction course of BCG. So at least five out of the six treatments--

Mark Tyson: Right.

Sam Chang: --followed by a second course either being another six weeks, or at least two out of three weeks. So in other words, two rounds of BCG and still having disease within a 12 month time period. Is that correct?

Mark Tyson: That's correct, exactly. And they were allowed to also have concomitant papillary disease. So there were some patients with concomitant TA disease and concomitant T1 disease.

But in cohort C, everybody had to have CIS. It's a very high risk phenotype, very difficult to treat population. And patients in the BOND trial, they underwent six induction cycles, six induction doses of Cretostimogene, followed by the three weekly maintenance doses every three months for a year and then every six months for years two and three. And that regimen was born out of the phase I data, suggesting that regimen at this dose was the best in terms of complete response rates.

Sam Chang: And not too, obviously, dissimilar from BCG, a treatment rationale and scheduling that really is not unfamiliar for practicing clinicians. And so--

Mark Tyson: It's very familiar.

Sam Chang: Yeah, absolutely. And so give us an idea regarding the primary endpoint, then, was a complete response, I'm assuming, and kind of what were the key findings?

Mark Tyson: Yeah, so it's complete response rate was-- and any time point was a primary endpoint that centrally confirmed in terms of pathology, and mandatory biopsies were done at 12 months. So those are all really, I think, important strengths of this study. And the key findings for that efficacy-evaluable population were a complete response rate at any time point of 75.5%. In my opinion, that number really doesn't mean all that much to patients. That's obviously what the FDA is looking at.

Sam Chang: Sure.

Mark Tyson: But in terms of what percentage of the cohort is doing well at a year, 46% were disease free at a year, and then at two years, 37.7%. Other really important findings-- progression-free survival was 97% plus. Cystectomy-free survival was 84.5%, really showing, highlighting, I think, Cretostimogene's bladder-sparing potential.

Sam Chang: And how was it tolerated?

Mark Tyson: Very well. The trial, in my personal experience, I didn't really see much side effects, maybe some intravesical-related, bladder-related side effects for a day or two. But overall, from a trial population, almost all grade one, grade two AEs. There were no grade three or higher treatment-related AEs, no deaths, no treatment-related discontinuations.

There were a couple of grade 2 SAEs. One patient developed non‑infective cystitis. Another patient had clot retention. But overall, very well tolerated. And I think one of the biggest illustrations of that was 97% of patients were able to complete all--

Sam Chang: So, finish their regimen.

Mark Tyson: Finish the regimen.

Sam Chang: I mean, think about-- compare that to the days when we initially looked at BCG and maintenance, where 16% to 17% got through the whole three year--

Mark Tyson: Right.

Sam Chang: --regimen. So the tolerance of this seems actually quite high as well as kind of the day to day side effects don't seem to be significant, which is, I think, really important to these patients as they try to determine kind of the next steps.

Mark Tyson: And I think that's rooted in the mechanism of action.

Sam Chang: OK.

Mark Tyson: Yeah. I think the virus is only replicated in RB pathway‑deficient tumor cells. And so if it's a normal cell, theoretically, E2F1 or E2F and RB are bound. E2F is not free to drive the promoter in the vector. And so the virus doesn't replicate in normal cells. And I think that's partly why it's so--

Sam Chang: And then there's a GM‑CSF role as well.

Mark Tyson: There's a second component, right. Yeah, the transgene expression of GM‑CSF primes that tumor specific immunity in the tumor microenvironment. And it's a dual mechanism of action, a one‑two punch of direct targeted tumor cell lysis plus immune activation.

Sam Chang: Right, and then that, at least by theory, then, you are hopefully getting then longer term responses because you've actually initiated something that will have immunity and have some memory for a period of time.

Mark Tyson: Exactly, and we saw that in the swimmer's plot that we presented in the plenary. You saw a number of patients who maintain their durable, complete response well beyond the treatment period. So they'd gone-- there's one patient who's out 45 months, so pretty far out. And I think that's because there's some element of immune response that's mediating this long term disease‑free survival.

Sam Chang: So as you presented this data-- and obviously, there's been a positive buzz with all these different treatment options for patients with BCG‑unresponsive disease. What next? Should this be also considered for BCG‑naive patients or perhaps intermediate risk patients? I know there are ongoing trials that are going, but kind of from your point of view, mechanism of action, and physiologic input, what do you think makes this attractive in terms of being able to actually employ this in your practice?

Mark Tyson: Well, I think it's helpful that it's familiar. It follows, like you said, along the kind of BCG line of workflows that we've implemented for decades in our field. It's given by the nurses. It's not difficult to tolerate.

All those reasons that you mentioned earlier, I think, are the reasons why that the company, CG, is exploring using it in intermediate risk and in the PIVOT‑006 trial and then in high risk patients that are naive-- CORE‑008, for example. There's a whole portfolio. They're really expanding who they're testing this in.

So I think the next steps for this drug, I think-- I'm hoping that-- who knows when it's going to be reviewed by the FDA? The company hasn't shared that with me. But my hope is that this is in practice in the next year or two, and we're using this as a monotherapy for BCG‑unresponsive CIS.

But beyond that, CG is considering rational drug combinations in CORE‑008. They're testing Cretostimogene in combination with gemcitabine. And so I think we could potentially see Creto be a backbone therapy for a number of rational drug combinations.

With the combination therapies, especially as we've learned in the AUA, the combination of different types of immune stimulators, possibly chemotherapy, possibly BCG, you have all these alternative options that add combination therapies. Only makes sense. But at this point, obviously, the attractiveness of a monotherapy, intravesical, is something that's familiar.

Patients would obviously prefer this as opposed to bladder removal and cystectomy. And the fact that there's a chance for-- a significant chance for long term durability really makes this an attractive alternative. As you counsel these patients now currently, let's look at our crystal ball and say, OK, this has been approved.

It's now available. How do you balance this with clinical trials, with other FDA‑approved indications? Because there are other intravesical instillations that are also-- how do you balance? How do you sequence? It's probably unknown at this point, but kind of what are you going to have in terms of a rationale behind that?

Mark Tyson: So in my practice I'm currently using Nadofaragene. I'm also using Nogapendekin. We have a whole portfolio of clinical trials, of which Cretostimogene is one. For those high-- for those very high risk, T1 phenotypes, especially if there's prostatic urethra involvement or upper tract disease, I'm still pushing cystectomy.

Sam Chang: No, I agree.

Mark Tyson: I think that bears repeating. As a field, we kind of-- I don't want us to lose sight of the fact that many of these patients are best served with upfront cystectomy.

Sam Chang: I think that's an important message to end the session with is that there are certain individuals that are going to be better served, actually, without these medications, better served in terms of risk of disease and risk of progression, of going ahead and doing that cystectomy. And when you have those life‑threatening patient populations, I think you should offer them the best treatment upfront.

Mark Tyson: I totally agree with that, because I tell patients who have stage 1 BCG unresponsive disease, I have a lot of stage IV bladder cancer patients who would kill to have their disease be diagnosed at stage one. Now is the time to cure this. But in terms of sequencing it, for those patients who failed 5 plus 2 rounds of BCG, maybe they got a little bit of CIS that I've detected on blue light and completely eradicated, for that kind of population, maybe we're not ready to make that leap. I leave it up to the patient.

Sam Chang: Sure.

Mark Tyson: I tell them about Nadofaragene. I tell them about Nogapendekin. I tell them about Cretostimogene and Detalimogene; I talk to them about all the different trial options. And whatever is most convenient for them, whatever is most attractive to them, I support them. And I think until we have some empirical data to say that this is which drug we should use and whom and when, I'm going to continue that pattern of just letting the patient decide.

Sam Chang: Now, and having those options really is an algorithm‑changing, actually, situation. We didn't have all those options five, six years ago. So I think it really does emphasize the combination of trying to risk stratify carefully and safely and then being able to offer all the different options to our patients. So, Mark, always a pleasure to learn from you and gain knowledge and so excited about upcoming trials, especially under your leadership. So thanks again.

Mark Tyson: Thank you, Sam. Thank you for having me.