Sam Chang: Hi. I'm Sam Chang. I'm at Vanderbilt University Medical Center in Nashville, Tennessee. Often refer to Nashville as Nash-Vegas. And we're actually in Las Vegas. Finishing up after AUA 2025. And we're fortunate enough to have a true leader in urologic oncology, Dr. Mark Tyson. Mark is a professor at Mayo Clinic in Scottsdale, and it really started as being one of the key investigators in many, many important clinical trials.

We're going to focus actually on BCG‑unresponsive disease. So non‑muscle invasive bladder cancer. Patients who've had disease that have had BCG but continue to have disease. And let's talk about cretostimogene. You've obviously helped develop these trials and helped lead them. There's a cohort‑‑actually, P, C. Cohort P, looking at papillary disease. Tell us what you presented at the AUA and your key thoughts and findings.

Mark Tyson: Absolutely. Thank you for having me, Sam. I appreciate this opportunity to join you. BOND‑003 Cohort P is a single‑arm, open‑label study evaluating cretostimogene in patients who have BCG‑unresponsive, papillary‑only non‑muscle invasive bladder cancer. So this is a very difficult‑to‑treat population. They've had adequate BCG, which the FDA defines as at least five of six doses for induction and in at least two of three or two of six doses for a second round of maintenance or induction.

And these are patients that have a recurrence within six months of that final dose of BCG. So many of them have TA or T1, but nobody has CIS. And so that's a key distinction between cohort C, which is just CIS with or without papillary‑only disease. Cretostimogene is an oncolytic immunotherapy. It has two components to its mechanism of action. It enters the cell.

And if there's an RB pathway deficiency, either in RB itself or a pathway regulator either upstream or downstream of that, anything that silences RB, the virus can replicate. So in normal cells where RB is bound to E2F, there's no‑‑

Sam Chang: It doesn't replicate. So it's basically in the RB‑deficient cells that tend to be obviously associated with tumor cells as opposed to normal cells.

Mark Tyson: Right.

Sam Chang: So it tends to kill cells then. And then there's another mechanism of action?

Mark Tyson: Right. Right. So the second component, there is a transgene for GM‑CSF that's expressed from the vector. And that is a potent immunostimulatory cytokine which primes the tumor‑specific immunity within the tumor microenvironment. So it's this 1‑2 duality; 1‑2 punch, if you will, of direct tumor cell lysis plus immune activation. And that's why we think it's so well tolerated and so effective. Yeah. So these are patients that got an induction course of cretostimogene once a week for six weeks and then maintenance doses once a week for three weeks every three months for a year, and then every six months for years 2 and 3.

And the trial is a single‑arm trial, which is interesting because the FDA has been very clear that for registration purposes, for papillary‑only patients, randomization would be required and a high‑grade recurrence‑free survival endpoint, not complete response rate and duration of response, which are the endpoints, obviously, for cohort C.

And so it's a slightly different endpoint, but it's a similar design. And the company‑‑I don't think‑‑has intention to try to pursue FDA approval for papillary‑only disease. I think they're providing some prospective data to inform future clinical trials. And also we've seen these drugs make it into NCCN guidelines. These category IIb recommendations are based upon single‑arm design. So I think those are the two goals of cohort P.

Sam Chang: To get information, obviously, because honestly, probably the majority of patients we see do not have the CIS component. Although I think now, I think our pathologists are actually more active in searching for, identifying, mentioning CIS involvement or not. But there clearly is a significant number of patients that don't. So far then, in terms of the data that's been collected, tell me what the efficacy looks like.

Mark Tyson: Right. It's really, really good. So high‑grade recurrence‑free survival at 3 and 9 months is 90.5%. And there are two patients that‑‑

Sam Chang: 9 out of 10 patients.

Mark Tyson: Yeah. And there are two patients that are being re‑induced. Because cretostimogene, with an immunotherapeutic mechanism of action, re‑induction may make sense, unlike maybe chemotherapy, for example. So those two patients could even drive that up further.

Sam Chang: Number even, yes.

Mark Tyson: And I've got a lot of patients on this trial. I've treated 20 or so on cohort P. And it's very similar experience with cohort C.

Sam Chang: So well‑tolerated.

Mark Tyson: Well‑tolerated, seems to be very effective. I'm not sure that the biology of the papillary‑only cohort is quite as bad as those with CIS, and certainly would defer to your experience on that. But I think that they are still pretty high risk. And so this is a really impressive number, I think.

Sam Chang: Yeah. Yeah, I think that‑‑but this has been a persistently difficult population to treat, because we haven't really had a lot of information in the currently FDA‑approved medications. Really, the focus has been on CIS as opposed to this population. So gathering data only gives us more information for possibly treating these patients, and maybe even earlier‑stage disease. I know that CG Oncology is looking at actually earlier‑stage disease. I don't know if you want to comment on that, about ongoing trials looking at that population.

Mark Tyson: Absolutely. Yeah. So they have a trial PIVOT‑006, which they're studying. This as adjuvant therapy in intermediate‑risk patients. And they also have a trial‑‑a multi‑arm, multi‑cohort trial called CORE‑008, where they're studying cretostimogene as a monotherapy in BCG‑naive patients. They're studying it as a combination therapy with gemcitabine in BCG‑exposed and unresponsive patients.

And they're studying it as monotherapy in a naive papillary cohort as well. That hasn't yet opened but will probably later this year or early next year. So they're trying to explore multiple disease states.

Sam Chang: I mean, I think significant kudos for the clinical trials. Gaining evidence, determining, are there certain populations that would benefit more? And there might be populations that don't benefit as much, but gathering that data only serves our patient population in a better way, which we didn't have a few years ago, for sure.

So what do you think the next steps are now with this papillary‑only cohort? Obviously, longer follow‑up, gathering more patients, et cetera. What are the goals in terms of enrollment and that type of thing? Is it just going to be open, or is there a certain time frame or number of patients that want to be gathered?

Mark Tyson: Enrollment is doing very well. I think it's about 70 that we're targeting. And I don't think it's going to be open much longer. I mean, this is an opportunity for all of us to give patients free cretostimogene. So we're taking advantage of that and putting patients that are interested and that are eligible on trial to get it, because I think it'll probably be FDA‑approved, fingers crossed, in the next couple of years. And so why not get them free drug now?

Sam Chang: Absolutely. Absolutely.

Mark Tyson: But I don't think it'll be open by the end of the year. I think we'll be probably accrued so soon.

Sam Chang: Well, Mark, thank you so much for spending some time with us. Obviously, the leadership that you've played in multiple clinical trials really have served many, many patients so much better and giving them options that we really didn't have in the past. So we look forward to future trials as well. And look forward to spending some more time together.

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