Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Mark Tyson, who is a urologic oncologist at Mayo Clinic, Arizona. We're going to be discussing SUO 2025 late-breaking abstracts and data that Mark presented at the recent SUO meeting. Mark, thanks so much for joining us at UroToday.
Mark Tyson: Thanks for having me, Zach. Glad to be here.
Zachary Klaassen: Why don't you roll through some slides? We'll cover the background and the top line results from Cohort P, and then we'll have a little Q&A after that.
Mark Tyson: That sounds good. Yeah, as you mentioned, this is Cohort P of the BOND-003 study. It's a single-arm, open-label trial evaluating cretostimogene monotherapy in patients with BCG-unresponsive papillary-only non-muscle-invasive bladder cancer. Just for the sake of your viewers, I have no conflicts of interest with CG Oncology. Just maybe a brief second on mechanism of action. This is an oncolytic adenovirus. It enters the cell through the Coxsackie and adenovirus receptor, and it exploits the biology of Rb pathway-deficient tumor cells. So any mutation in Rb or anything that silences it, either upstream or downstream regulators, can result in a favorable environment for replication. And so it selectively replicates in those cells to cause direct tumor lysis through E2F-1-mediated replication.
And also, the vector expresses GM-CSF, which stimulates dendritic cell activation as well as primes tumor-specific immunity. And so this combination, this one-two punch on the mechanism we think is the reason why it's so effective and well tolerated. And there's a big unmet need in the papillary-only space. Recall, all of the FDA-approved agents in this space are approved only for CIS. And so there are a number of drugs that we're currently using off-label for this. The idea behind Cohort P is to provide prospective data for cretostimogene in this setting. And there's a recent meta-analysis that showed some nice benchmarking data for high-grade recurrence-free survival. 73% at three months, 58% at six months, and 48% at 12 months. So clearly more work to do. Just briefly, just for context, Cohort C has read out a couple times now.
This top line number for the BCG-unresponsive CIS population is 75%, and the intention-to-treat population at one year and two years is 46% and 42%. So these are really good for monotherapy. Not a lot of progressions. 96% were progression-free. Not a lot of cystectomies. Most patients avoided that successfully. And those who did have a cystectomy, 83% of those were either T0 or non-muscle-invasive at the time of cystectomy. So this drug clearly has very good activity. No grade 3s, no treatment-related discontinuations, and no deaths, so it's very safe and tolerable as well. So that was the basis really for Cohort P, the design of which is very similar to Cohort C. These are patients that are enrolling on a single-arm, open-label study, and their treatment is very similar. They get induction weekly for six weeks, followed by maintenance every three weeks for every quarter in the first year and then every six months in years two and three.
Unlike Cohort C, where complete response rate and duration of response are the endpoints, Cohort P's primary endpoint is high-grade recurrence-free survival. As expected, most of these patients are elderly, white, and male. There were 56 patients that were eligible at the last data cutoff, 51 of which had efficacy evaluable data. 96% of these were from the U.S. A very high-risk population. And the median number of instillations for BCG was nine, with 41% of these being T1. So at a top line number and a median follow-up of six months, the three-month high-grade recurrence-free survival was 95.7%, at six months it was 84.6%, and at nine months it was 80.4%. Eight patients were reinduced. Those CRs are ongoing. And we see consistent efficacy across the high-grade Ta and high-grade T1 subsets. No patients have undergone radical cystectomy yet and no patients have progressed to muscle-invasive disease. Similar to Cohort C, we saw very good tolerability and safety. There were no grade 3 treatment-related adverse events, no treatment-related discontinuations, and no deaths, and 98% received all protocol-defined treatments.
This was a big effort by a lot of different centers across the United States and Japan. And I think the way I would just conclude this presentation, Zach, is just by saying top line results mirror C. These are excellent results that we're seeing, and these responses are maintained, even in the highest risk T1 subset. It's a very good safety profile as well, and obviously we're going to need to see long-term follow-up. And this was the basis. The Cohort C was the basis for the rolling BLA submission that CG filed earlier this year with the FDA, so I'm hopeful that we'll be seeing the FDA render a decision hopefully sometime next year. Here are our key collaborators. Just want to say thank you to the patients and their families and to all my partners in this work that are listed here. Zach, I'll stop there and take any questions.
Zachary Klaassen: Awesome, Mark. As always, great presentation and highlight. This is such an important cohort, I think. There's some debate as to if pathologists are looking for CIS hard enough in these patients. And so we see Ta-T1 recurrent BCG-unresponsive patients all the time in our clinics. And I think what I'd like to question on too is that T1, 41%, this is a high risk of the high risk, and to see those efficacy results. What are your thoughts on how this may add another really safe and effective and well-tolerated treatment into our armamentarium?
Mark Tyson: Yeah, that's an important question. By the way, all of these patients have been completely resected, including T1s, who had to undergo a repeat resection prior to trial entry. And so these were ultimately patients that the investigators felt comfortable putting on the trial, and these were patients that were comfortable going on trial. So there's definitely some selection there. I mean, there's going to be some very, very high-risk patients in there, no doubt, but hopefully still as a field for our very super high-risk patients, we're still choosing cystectomy.
Zachary Klaassen: Sure.
Mark Tyson: But for those patients who don't want cystectomy, or for those patients who can't otherwise get it, or for those patients who want to try something other than just BCG, then cretostimogene represents a pretty good option for these patients. I had a very good experience on trial. I think we need longer-term data before we can really take that to the bank. But I'm optimistic based upon these curves that we're seeing now, 80% high-grade recurrence-free survival at nine months is very good. And so if that continues to map out like we think it will, then this will represent a very good adjuvant treatment option for those patients.
Zachary Klaassen: Yeah, absolutely. I think when you look at the job that CG Oncology has done is really looking at the whole landscape. We've seen BCG-unresponsive, both with and without CIS now. We have BCG-exposed we're getting data on. We have low-grade intermediate-risk. PIVOT-006 accrued all the patients waiting for data. We're really seeing a landscape sort of not shift, but a magnitude of benefit here with cretostimogene. Maybe just speak to that a little bit.
Mark Tyson: Yeah. So I think that CG's regulatory strategy has been a very comprehensive one, like you noted. The data for intermediate risk in the end might be the strongest because it's a randomized phase 3.
Zachary Klaassen: Sure.
Mark Tyson: Comparing cretostimogene to observation from that trial we'll get average treatment effects of cretostimogene in that setting, which I think is a bold strategy and I think that will pay off well for CG. But in the unresponsive CIS and in the unresponsive papillary-only cohort, we just have single-arm data. So determining the average treatment effects in those populations are a little bit more difficult because we don't know the counterfactual. But certainly when we see the numbers that we've seen in these single-arm trials be as good as they are for cretostimogene, then I think it obviously has a bright future in our field. CORE-008 is another really good one that you mentioned, BCG-naive and BCG-exposed patients with cretostimogene monotherapy, as well as in combination with gemcitabine. And I'll be exciting to see how that data evolves as well. So yeah, we do have prospective data in virtually every disease state that you can imagine, I guess, except for low risk and that speaks to just the comprehensive nature of the CG portfolio.
Zachary Klaassen: Absolutely. Mark, congratulations on another great cretostimogene presentation at SUO. Any final thoughts, any concluding statements for our listeners?
Mark Tyson: No, I appreciate you having me on, Zach. I think, like I said, the rolling BLA has been submitted to the FDA. I think we'll hear from them next year. And these data are currently being submitted in the manuscript form, and hopefully we'll see that out early Q1 of next year.
Zachary Klaassen: Wonderful. We'll look forward, Mark. Thanks so much again.
Mark Tyson: Thanks, Zach.