BOND-003 With Dr. Mark D. Tyson: Cretostimogene for BCG-Unresponsive Bladder Cancer

Mark D. Tyson, MD, of Mayo Clinic, discusses the data from cohort P of the BOND-003 trial, exploring the potential of cretostimogene grenadenorepvec in treating papillary-only BCG-unresponsive, non-muscle-invasive bladder cancer. He explains the trial’s focus on providing the urologic oncology community with data for informed treatment decisions, the unique mechanism of action exploiting RB pathway deficiencies, and the broader implications for bladder cancer care. Dr. Tyson also sheds light on FDA guidance that spurred innovation in this field and the critical importance of trials aimed at preserving bladder function in high-risk patients.

Transcript

What inspired the development of the BOND-003 Cohort P study, and how does cretostimogene address unmet needs in the treatment of BCG-unresponsive high-risk, non-muscle invasive bladder cancer?

Dr. Tyson: Thanks for having me here. Delighted to join you. So I think Cohort P was inspired out of the success that we observed in Cohort C. So recall, bond three is a single-arm open-label trial studying cretostimogene, grenadenorepvec monotherapy in patients with BCG-unresponsive, non-muscle-invasive bladder cancer. And these are patients that meet that classic definition of unresponsive CIS. So the inspiration for Cohort P really was born out of the excellent response rates that we were observing in Cohort C, which I’ll just remind your viewers that all that data was presented at the SUO in December. And top-line data showed pretty good responsiveness, 75% at any time point. And then that durability piece was key as well with the 27 month and counting meeting duration of survival. So we know the drug has activity in the BCG-unresponsive CIS space. The question under study for Cohort P is whether that same activity is observed in papillary-only patients.

And so these are the essentially the same definitions for BCG-unresponsiveness, but these are patients that do not have any evidence of CIS on their pathology. They just have a papillary lesion as high grade and unresponsive. It is a single-arm trial. So the FDA has been pretty clear in their guidance so far that single arm trials or papillary-only studies would require randomization to determine treatment effect. So Cohort P does not have registrational aims. CG is not going to the FDA and requesting approval for use in papillary-only patients. But the idea, the inspiration behind Cohort P really is to provide the urologic oncology community data to use in guiding treatment decisions, potentially off-label in the future if cretostimogene does receive approval for the CIS population. And this is something that is being done for other drugs in this space as well. So I think in a nutshell, that’s the inspiration.

Can you elaborate on the dual mechanism of cretostimogene and how these mechanisms contribute to its therapeutic potential?

Dr. Tyson: I’ll start with the second half of that question. It’s not just therapeutic potential, but also side effect profile. So the mechanism of action is why we think the drug is so effective in this space as well as so well tolerated. That’s because, as you pointed out, cretostimogene exploits the biology of RB pathway deficient tumor cells. And it can be not just deletions in RB itself, but it can be any pathway regulator upstream or downstream that silences RB. That leads to the E2F transcription factor being unbound to RB and then transcribing the essential viral genes in cretostimogene that leads to its replication. So in RB pathway deficient tumor cells, the virus replicates, it directly kills those cells, and then viral progeny is released. The tumor microenvironment is enriched with tumor antigens, viral antigens, as well as the GM-CSF, which is a trans gene that’s in the virus as well.

And all of that leads to direct tumor toxicity and also immunotherapy effect from the GM-CSF and the viral antigens and tumor antigen release as well. So there’s kind of like a one, two punch component to the mechanism of action, but none of that happens in cells where RB pathway is intact. So theoretically, all of the normal urothelium is not affected by the replication of cretostimogene.

How did you define the specific patient population for this cohort (BCG-unresponsive Ta/T1 without CIS), and why is this subgroup particularly relevant for evaluating cretostimogene?

Dr. Tyson: You’re right. It’s a very specific population, I think. I’m not a businessman or a commercial type. I’m just an investigator on the trial. So it’s harder for me to answer those questions about why a specific population was targeted. But I think years ago, the FDA released guidance to help spur innovation in this space. There really hadn’t been nothing done in 20 years. Since the approval of valrubicin, there really was kind of this long gap with no activity. And the FDA recognized that there needs to be more work done in this space. And so they issued some guidance that said, for patients with CIS who’s not responding to BCG, and they coalesced with many of the experts in our field on what precisely that definition would be. And then they said, because these patients with CIS are entering the trial with active disease, a single-arm trial would be appropriate with complete response rate and duration of response as co-primary endpoints.

Well, that trial is a lot easier to run than a 1000 person randomized phase three. It’s a lot cheaper. So the question about why is this population targeted for all of these drugs? And the answer is because that’s what the FDA incentivized with their guidance years ago. And so that’s the why piece. In terms of the how, the FDA has stuck to this definition now as far as I know for going on seven years now, and I think it might’ve been in the works even a few years prior to that, but these are patients that have received adequate BCG. There’s two components of this definition. It’s the amount of BCG they receive, but it’s also the pattern of recurrence as it relates to the receipt of that BCG. So adequate BCG is defined as at least five of six of an induction course plus two of three or two of six repeat maintenance or induction courses.

And so if somebody’s received seven doses of BCG, usually kind of within six months to a year, in other words, somebody couldn’t have gotten five five years ago, and then two now. But if they’ve gotten it within six to 12 months, and each of the protocols vary a little bit on that, and then they recur with CIS within a year or papillary disease within six months, then they would qualify as unresponsive. You can also get in with just five of six induction BCG if you have a T-one recurrence immediately after induction. That’s the third piece of the definition. So that’s the how they are defined.

And then to your last point, why is this group, subgroup particularly relevant? It’s because they’re the most difficult to treat. These are patients that are heading towards cystectomy. Historically, that’s what we would do. I’ll just tell you parenthetically that the cystectomy volume in my practice is going down. It’s palpable, and that’s a good thing. I’m actually very happy about that. And so I think that’s because a lot of these patients, the appropriate ones, are being funneled to the trials to try to save their bladder and their life without having to remove their bladder.