Gary Steinberg: Thank you very much for the invitation. And this is a multi-centered trial, mostly a US trial. It was also run through the SUO-CTC, but we're going to talk about the results from Phase 3 of BOND-003 Trial Cohort C. And we're going to talk about a subset, the cystectomy-free survival following cretostimogene grenadenorepvec in high-risk BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ. Just a little background, as we know, radical cystectomy remains a guideline recommended treatment for high-risk BCG-unresponsive non-muscle-invasive bladder cancer. Though effective in controlling disease, it carries substantial morbidity. And as we all know, a significant number of patients would prefer to keep their bladder rather than lose their bladder, although there's some recent data that may refute that from the CISTO trial that was recently published in the JCO. Anyway, there's a considerable unmet need for effective, well-tolerated bladder-sparing treatment options for patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with dual mechanisms of action. It selectively replicates in and lyses cancer cells while amplifying the immune response against bladder tumors. The BOND-003 is a pivotal phase-three trial designed to evaluate cretostimogene.
We report outcomes from cystectomies performed on this cohort. There were 112 patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ plus or minus high grade TaT1 disease, and all of the visible TaT1 disease was resected prior to treatment. The response assessments would include cystoscopy, biopsy as indicated, and cytology every three months for the first two years and every six months starting year three, all responses are essentially confirmed. There was an all patient biopsy mandated at 12 months. And the cystectomy-free survival was calculated from the first study treatment to cystectomy or censoring, whichever occurred first in the efficacy analysis set. And then this is just a diagrammatic of the study. Patients were given an induction course once a week for six weeks. One of the things that is important when you're giving intravesical cretostimogene is that there is a step where you wash out the bladder, you want to knock off the gag layer to improve transfection of the oncolytic immunotherapy. Having said that, we have streamlined the washout to where it's now just a 15-minute dwell time prior to instilling the cretostimogene. And there is some newer data that's been presented at other meetings demonstrating that that's actually even more effective for the efficacy with cretostimogene. Importantly, in this trial, if patients had persistent carcinoma in situ or high grade Ta disease at their first three-month assessment, they were able to get a second induction. And that there was a maintenance every three months for the first year of three weekly instillations, and then every six months for years two and three, again, three weekly instillations at the maintenance therapy.
And the endpoints were complete response at 12 months, duration of response, recurrence-free survival, progression-free survival, cystectomy-free survival, and safety. Just showing in a very pretty slide how oncolytic immunotherapy with cretostimogene works. It's a dual mechanism of action. And the oncolytic immunotherapy cretostimogene selectively replicates in and lyses bladder cancer cells that have pRB pathway abnormalities. So that's pRB, p16, p21, p53, of which approximately 75 to 80% of high-risk non-muscle-invasive bladder cancers, especially the high risk, have those perturbations. More importantly, there's also the coxsackie adenovirus receptor from cretostimogene that binds to the cancer cells selectively as well. This causes viral killing, tumor cell killing, which creates a chain reaction of cancer cell death. The viral progeny was spread into two additional tumor cells. But more importantly, you create tumor antigens and neoantigens, which are recognized initially from the innate immune system to the adaptive immune switch. Cytokines and antigen release activates T and B cells inducing immunologic memory because the cretostimogene has the GM-CSF gene as well as part of the construct, again, providing antigen-presenting cells to T cells, giving a specific cancer-specific immunologic cell death. The BOND-003 Cohort C has 24-month data now. We see compelling complete response on 24-month durability data. The overall complete response at any time was 75.5%.
Again, when we look at other treatments such as pembrolizumab, ADSTILADRIN, BCG, and ANKTIVA, as well as INLEXZO, which is the TAR-200 intravesical pretzel with gemcitabine, we see that the efficacy and complete response rate of cretostimogene is quite robust. More importantly, the complete response rate, not the Kaplan-Meier, but the intent to treat at 12 months is 46.4%, or 51 out of 110 patients are disease-free. And that at 24 months, importantly, 46 out of those 51 patients or 46 out of the entire 110 patients are still a complete response. And again, this is quite favorable when you look at the results from the other FDA approved agents. More importantly, as we'll see in the next slide as well, few patients progressed to greater than or equal to T2 or muscle-invasive disease. The median follow-up time of this trial is 25.8 months. The median duration of response is 27.9 months and is ongoing. 92 of 110 patients preserved their bladder. And as we'll see, I think in the next slide, of the patients that did undergo radical cystectomy, 15 of the 18 patients were pT0 or less than muscle invasion, a pTa or pT1 non-muscle-invasive bladder cancer at the time of cystectomy, and 96.4% of patients were free from progression to greater than T2 disease. And then this slide just looks at it again. As we can see, few patients, only 18 patients underwent cystectomy. Anytime after the first recurrence, within the first year of recurrence, 17 of the 18 patients underwent cystectomy within the first year of the recurrence.
Overall, we see the time to cystectomy post-recurrence for progression in weeks, and the median time is 20 weeks. And then looking at the stages, again, majority were non-muscle invasive. There was one patient with nodal metastases and two patients with muscle invasion with node negative. Again, what Ashish alluded to initially was the durability. And so patients want a complete response, but what's most important is the patients want durable complete responses. And so if you had a complete response, your estimated duration of response probability at 12 months was 64.2%, and believe it or not, 60% at 24 months, which is really quite different. If we look, for example, at the ADSTILADRIN data, at 12 months, we had approximately 24 to 25% complete response. When you went to 24 months, it was down to 19%. And at 36 months, it was down to 13%. Clearly, with the mechanism of action, we believe that there's a T cell memory that's being created, which is a principal component of the durability of the response. Last but not least is the tolerability. Cretostimogene is well tolerated. Most adverse events were Grade-1-to-2, 0% Grade-3-or-greater treatment-related adverse events or deaths. Median time to treatment-related adverse event resolution is one day. No treatment-related discontinuations. 1.8% or two patients had serious treatment-related adverse events, Grade 2, and 97.3% completed all protocol-defined treatments.
And again, most of the side effect profile is lower urinary tract symptoms, which you'd expect to see in any intravesical therapy, especially a group of patients that was heavily pretreated with a BCG and/or BCG plus additional treatments. So I think that to sum it up, the FDA guidance has helped the urologic community and the patients to identify new therapies. These new therapies are using novel intravesical agents, and we're seeing response rates that we certainly haven't seen before, especially in these very hard to treat patient populations. And certainly, even though the CISTO trial may imply that patients were okay with or preferred having their bladder removed rather than bladder surveillance and bladder preservation, the important thing about that trial is that none of the newer treatments that are FDA approved, as well as in study were allowed on that trial. I think that if that trial would be done today and allowing patients to try these new novel therapies, which are, I think, a major step forward in terms of complete response and durable response, that more patients would most likely prefer to keep their bladder. As we all know, even with continent urinary diversion, it doesn't work nearly as well as your native bladder. And I'm going to stop there and let Ashish ask me any questions.
Ashish Kamat: Thanks so much, Gary. Always, always a pleasure to hear you, and the way you distill down the data is always enlightening. We've come a long way, right? I mean, I remember chatting so many years ago when pembrolizumab was being discussed, and we were all scared that if you don't take our patients right away to a cystectomy at the first sign of non-response or recurrence after being BCG-unresponsive, it would translate into really poor outcomes for them. And now we are seeing, and of course, in the CG trial, in the BOND studies, reinduction was allowed because we're recognizing that it's not unsafe for the patient. Can you share with us a little bit your insight as to how your view of this has changed over the last decade or so?
Gary Steinberg: Yes. There's no question that we were relying on a lot of old data. We still are relying on a lot of retrospective data, single-institutional trials, even if some single-institutional trials were compared. And that one of the things that I think that the urologic community has done, the International Bladder Cancer Group, the Think Tank and the Bladder Cancer Advocacy Network, is begin to drill down more about the natural history. And I think that we can safely say that today, patients can have a second-line treatment and even potentially a third and fourth line treatment as long as we don't demonstrate muscle-invasive disease. Yes, there needs to be careful surveillance, and we do need to understand that we potentially need additional imaging such as CT scans to pick up those patients that even though cystoscopically they don't seem to be progressing, that they are on imaging, whether it's CT or MR.
And I think that one of the really newer innovations are going to be looking at urinary-free or cell-free DNA and circulating tumor DNA to really try to drill down to patients that are at greatest risk. But I think that we do have time. I think it is safe. I do think that not all patients' immune systems work as quickly as others, and so that I think it's reasonable to give patients a second induction if they don't have a complete response. Having said that, we do need to be aware and be careful and survey these patients carefully. As I've told many, many patients, we can cure your cancer with a high likelihood if we take your bladder out, but that it may be overkill and you may not necessarily need that, especially when you consider that we're dealing with an elderly patient population. I think that I am disappointed that even though we introduced continent urinary diversion in the late '80s, we still are not doing continent diversions as well as we should. We still see that the vast majority of patients are getting ileal conduits. And again, I think that while ileal conduits work very well, patients would prefer to keep their bladder, and that there are a lot of associated side effects of having your bladder removed, social, physical, socioeconomic, financial, and I think that we kind of have to put it all together.
Having said that, we should not be afraid to perform radical cystectomy. And that, as we've seen in the past, when we've guessed wrong, it does have direct consequences, and that patients do progress from non-muscle invasive to muscle-invasive and metastatic disease. And all too often at tertiary centers, we'll see patients that have had BCG after BCG after BCG and then present to the university with a node-positive disease. I think we have to be careful to avoid that, but there's no question that if we follow these patients with a careful algorithm and evaluation, that we do have time to try at least one, if not two novel therapies to see if we can preserve their bladder.
Ashish Kamat: Yeah, Gary, you're being modest. You mentioned different organizations and the IBCG, and of course, you're an integral part of all of these, and you've been leading the charge and trying to understand what we're doing right and what we're doing wrong for years. So I do want to make a public shout-out to all the effort that you've put in as well. We could chat forever, but I'm going to ask you one last question in the interest of time. In the patients on these studies, and for example, in this study that ended up with a radical cystectomy, most of them were non-muscle invasive. Do you think it is a counseling issue? Do you think today we are at a stage where we could tell patients, "Hey, we shouldn't be thinking of BCG-unresponsive one treatment cystectomy. We should thinking first line, second line, third line?" Any closing remarks there for the audience?
Gary Steinberg: There's no question the patients want, and I think they deserve at least a second line, if not a third line. Once we start talking about a fourth line, we do increase that risk that they're going to progress to muscle invasion and metastasis. Having said that, we desperately need urinary markers. ctDNA is good for systemic disease. Hopefully, we don't wait until the ctDNA is positive in these patients, but looking at the urinary-free DNA to identify early indications of more aggressive disease. And again, I think that experienced urologists that see a lot of bladder cancer patients, we kind of have an overall gestalt about who's not going to do well, but I think that we need to continue to work on better biomarkers and identification of those patients at highest risk. Because as we know that those patients can be cured of their disease, especially if they've got organ-confined disease in the 90 plus percent range, and we need to keep that in mind, especially when we know how deadly urothelial cancer can be and metastatic disease, while we have much better systemic therapies is still a very significant illness.
Ashish Kamat: Well said. Gary, as always, thank you so much for taking the time. Always a pleasure.
Gary Steinberg: Thank you very much.