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Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday with Dr. Mark Tyson, who is a urologic oncologist at Mayo Clinic, Arizona.

Today, we're going to be speaking about data presented by Mark at SUO 2024, specifically BOND-003, a multinational single-arm study of intravesical cretostimogene for the treatment of high-risk, papillary-only, BCG-unresponsive non-muscle invasive bladder cancer. Mark, great to have you back on here today. Thanks, as always, for your time.

Mark Tyson: Thanks for having me, Zach. I'm delighted to be here. Thank you for the kind introduction. The BOND-003 abstract was updated at the SUO this past year. And just for your listeners and viewers, just as a reminder, the BOND-003 trial is studying cretostimogene grenadenorepvec monotherapy in patients with BCG-unresponsive non-muscle invasive bladder cancer. And I thought it might be helpful just to review the mechanism of action briefly.

It's a conditionally replicating virus. It's an oncolytic immunotherapy. And it selectively targets and destroys cancer cells. It does this by exploiting the biology of Rb pathway-deficient tumor cells, either upstream or downstream of Rb. And the slide I'm showing here is essentially how it works.

It enters a bladder cancer cell. And in Rb pathway-deficient tumor cells, where the Rb protein is silenced, this virus has the opportunity to replicate and directly kill the cell. Then, through the replication of the virus as well as cell death, the tumor microenvironment is enriched with the transgene expression of GM-CSF, which is a cytokine that primes tumor-specific immunity.

So it's a really interesting treatment modality that has a one-two punch in terms of the mechanism of action. Just by way of brief review, the BOND trial is a single-arm, open-label phase 3 study. It's about 112 participants that meet the strict FDA criteria for BCG-unresponsive disease.

Patients get weekly induction—six weekly inductions for the induction period. If they don't have a complete response at the first disease assessment, then they can get a second induction course. If they do have a complete response or if they respond to the second induction course, then they go on to receive maintenance at 3, 6, 9, 12, and 18 months.

A mandatory biopsy is done for these patients at 12 months with a central path review. And as you mentioned, enrollment is complete, and Creto has been given fast track and breakthrough designation therapy status by the FDA.

In terms of baseline characteristics, the trial, as we presented at SUO last year, is very representative of a high-risk non-muscle invasive bladder cancer population—it is predominantly elderly white men. But only 64% of patients were enrolled from the U.S., so it's a pretty diverse racial and ethnic background as well.

And patients, as you can expect, are heavily pretreated with BCG. The median number of prior BCG doses was 12. About a third had also received prior intravesical chemotherapy. And about 7% had also undergone systemic immunotherapy.

In terms of efficacy, which I'm showing here on the slide now, as of the data cutoff of September 30, 2024, in the efficacy-evaluable population—which we defined as meeting the FDA criteria for unresponsive disease, having at least one dose of Creto, and then getting a response assessment at three months—

This, at a top line, showed a complete response rate of 74.5% at any time point, and the range of plausible CRs being between 65% and 82%. And somewhat very importantly and also very encouragingly, at 12 months, 47% of patients were in CR, with 25 confirmed responses at 24 months. So this appears to be a very durable monotherapy.

But like I said, beyond those response rates, there is this demonstrated sustained efficacy. The median duration of response exceeds 27 months and has not yet been reached.

And if patients were in complete response at a year, they're very likely to maintain that at two, as you can see here in the Kaplan-Meier curve. At a median follow-up of 14 and a half months for responders, 63.5% maintained their complete response at 12 months, and 56.5% maintained their complete response at 24 months.

So this is a really important figure to us as investigators and, I think, to CG Oncology. It represents the potential role for Creto in driving this innate-to-adaptive immune switching, which you can see with this long tail on the KM curve.

In terms of safety and tolerability, it's pretty well tolerated—mostly grade 1, grade 2 treatment-emergent adverse events. No grade 3s. No deaths. There were a couple of grade 2 SAEs in noninfectious cystitis and a clot retention in a patient. But overall, pretty well tolerated.

All the patients, for the most part, are able to receive the treatment in clinic. And it obviously fits within the existing induction and maintenance paradigm that our nurses are used to with BCG. So with that, I will stop and take questions.

Zachary Klaassen: Mark, thanks so much for that update on cohort C. We're starting to see some really durable responses and deep responses. And when you combine this with the tolerability, we're seeing updated data, as you mentioned, September 2024. As we move forward and continue to get updates, how does this sort of place Creto in this BCG-unresponsive setting?

Mark Tyson: Yeah. It's a very exciting time for all of our bladder cancer patients, obviously with the approval of several agents already and then a couple of really promising ones in the pipeline. I think the answer to where this positions is going to depend upon a lot of different things.

And I think there's more work to be done, especially by our TM colleagues, who are going to really do a deep dive on all of these treatment modalities and determining which of these work best in whom and when. But for right now, I think of cretostimogene as a very well-tolerated drug. And I think of it as a very effective drug.

And so I think those two features of it are going to position it towards probably the top of most people's treatment armamentarium. Now, obviously, it's going to depend on cost. It's going to depend upon availability. And each practice is going to be a little bit different. But I think, based upon the data that's been presented so far, I think most of the urologic oncology community is going to view cretostimogene favorably.

Zachary Klaassen: Yeah, absolutely. I know there's a cohort enrolling as well. This is papillary only, using the same treatment regimen, which is very exciting too because we see a lot of just papillary high-grade tumors.

So let's fast forward. Let's assume that we get a nice broad approval for CISTAT1. First of all, give us an update on cohort P and maybe what the landscape would look like if we have a broad coverage for all of those entities.

Mark Tyson: Yeah, so cohort P is enrolling very well—I think maybe even slightly ahead of schedule. It is a single-arm, open-label design. And the FDA has been quite clear for papillary-only patients a randomized design would be needed for registrational intent.

So this is not a registrational arm of BOND-003. This is a really well-done prospective cohort study to demonstrate efficacy in this very difficult-to-treat population. And I think the goal is to generate data for those of us who see a lot of these patients to use when determining what the next best steps are for these patients.

So I think, depending on what it shows, I think I could see this elevating potentially to the guidelines or potentially just used off-label based upon the data from cohort P, much like we do now with nadofaragene.

Zachary Klaassen: Yeah, absolutely. Thanks so much for the great updates on cohort C. We're excited that cohort P is enrolling quickly. And I know we'll be seeing data from that cohort, I'm sure, soon. So, Mark, as always, thanks for a great conversation on UroToday.

Mark Tyson: Thank you, Zach. It's a pleasure to be here.