Read the Full Video Transcript

Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and it's a pleasure to welcome to the forum someone who needs no introduction, Professor Mark Tyson, who is joining us from the Mayo Clinic in Arizona. And Mark, thank you for taking the time to join us today and to talk about the results of CG0070, you can call it cretostimogene, and the BOND-003 results that you presented at SUO that have really gathered everyone's attention. And we're eager to hear your nuances and your behind-the-scenes take on the data after you present them to us.

So, Mark, take it away.

Mark Tyson: Well, thank you, Dr. Kamat. It's a pleasure to be here with you today, and I'm delighted to share these data, and so, thank you for the opportunity. As you said, we presented BOND-003 at the SUO in November,/December. BOND-003, for our listeners, is a single-arm, open-label, phase 3 registrational study of cretostimogene grenadenorepvec monotherapy for BCG-unresponsive non-muscle invasive bladder cancer. I have no conflicts of interest with CG Oncology.

So, what is creto? I'd like to just take this opportunity to unpack the mechanism a little bit. Creto is a conditionally replicating oncolytic adenovirus that's been designed to replicate in, and kill cancer cells. They've cloned the human E2F-1 promoter into the E1A promoter region of the adenovirus, and that drives the expression of essential viral genes, while restricting the replication to RB-pathway deficient tumor cells. So, tumor cells, bladder cancer cells, often have RB-pathway defects or defects in the pathways that regulate it, like p16. This virus selectively infects those cells and replicates in them, and then kills them, and thereby sparing normal tissue.

Creto also encodes the complementary DNA for GM-CSF, which is a potent cytokine inducer of antitumor immunity in animal models. And the primary way it gains access to the cells is through the coxsackie adenovirus receptor, which is expressed in all stages of bladder cancer, but high levels of expression have been observed in TA and CIS.

So, there are really two things going on at the cellular level here that I'd like to highlight. The creto enters the malignant cells where viral replication leads to tumor cell lysis and release of viral and tumor-specific antigens. And these antigens are picked up by the dendritic cells that present it to T cells, which attract more immune cells and potentiate the immunotherapeutic effect. So, we have two things here. We have cytotoxicity from the viral replication process itself, and then we also have a recruitment of the immune system through secondary measures, such as GM-CSF and attracting additional cytotoxic T cells, et cetera.

This mechanism of action is what formed the basis for multiple studies leading up to BOND-003, including BOND-002, which was a phase 2 study evaluating creto in the BCG experienced population, showing a six-month CR rate of about 65% in all comers in the intention to treat population.

That leads us to BOND-003, which is the follow-on registrational phase 3, evaluating creto in the BCG unresponsive CIS population, according to the definition that yourself and others put together for the FDA in a 2018 guidance. We did allow concomitant papillary disease in this study, but it had to be completely resected prior to study treatment. And importantly, as this isn't always the case in the unresponsive space, we did require mandatory biopsies of the bladder at 12 months, and that included five regions of the bladder as well as the prosthetic urethra.

The primary endpoint for this study was the complete response rate at any time point, and key secondary endpoints included the complete response rate at 12 months, duration of response, progression-free survival, recurrence-free survival, and cystectomy-free survival. And in terms of treatment, patients underwent six sequential weekly instillations of creto, followed by a second induction course for non-responders or maintenance for responders, and maintenance was at three, six, nine, 12, and 18 months.

In total, 116 patients enrolled in BOND-003, and this is the interim analysis of the first 66 with a cutoff date of October 5th, 2023. And as expected, a lot of these patients, on average, are white, male, and Medicare-aged. 18% of them had concomitant papillary disease. And the thing that I really want to point out here is that this is a heavily pretreated cohort of patients. The median number of prior BCG instillations was 14.4, and there were several other patients too that also had received pembrolizumab prior. So, heavily pretreated.

In terms of the primary endpoint, the efficacy analysis for all patients based upon the central path review revealed a complete response at any time point of 75.7%, with a confidence interval indicating a range of plausible CRs between 63 and 85%. In terms of the durability of response of the patients that had a complete response, 74.4% of them were durable to at least six months.

The swimmers plot here, I think, is a really helpful graphic. It shows a pretty impressive response rate that's ongoing for much of the cohort, out to about nine months. But the thing to really take away from this graph is the 31% of patients who did not respond to the initial induction course of cretostimogene, but then went on to respond to a second induction course. So, that underlies, we think, it underlies, the mechanism of action, the oncolytic immunotherapy, where the immune system response is changing from innate to adaptive, as we see with the second induction course of BCG.

In terms of toxicity, creto was really well tolerated. There were no grade 3 treatment-related adverse events, there were no deaths due to treatment, and there were no treatment discontinuations due to adverse events. We did see two grade 2 serious adverse events. Of course, these data will be updated as the data mature.

So, recognizing that this is an interim analysis and recognizing that comparing across populations is difficult due to underlying differences in those populations, creto would at least appear to compare favorably to the two current non-surgical co-standards of care for BCG-unresponsive disease. The 76% CR rate at any time point compares favorably to 51% that was observed for nadofaragene, and to the 41% that was observed for pembrolizumab. And the 64% CR rate at six months for creto monotherapy compares favorably to the 41% observed for nadofaragene and to the 36% observed for pembrolizumab.

Compared to other concepts in the pipeline like Roger Li's CORE-001 study, which is studying combination therapy with cretostimogene and pembrolizumab, the confidence interval presented at the SUO for creto monotherapy includes the point estimate from CORE-001. So, this is definitely something to watch over time as those two studies mature, because obviously the data that Dr. Li presented was really, really impressive. Compared to N-803 and BCG-combination therapy, creto monotherapy also compares favorably.

Just want to take a second, if I can, to highlight two amendments coming, which I think are really important. There's a treatment extension phase for patients that have responses at 18 months, who can continue on into years two and three with maintenance therapy. And then there's also an addition of a papillary cohort coming, a 70-patient papillary cohort, Cohort P, where we give the same dosing schedule as before, obviously without the repeat induction for non-responders.

I also think it may be worth a second or two highlighting a really great collaboration between the SUO-CTC and CG Oncology. There's a trial run by Dr. Rob Svatek, PIVOT-006, studying cretostimogene in the intermediate-risk non-muscle invasive bladder cancer space.

I'll just stop there and just, I'd like to thank the study coordinators, the nurses, the patients, and their families, and our key collaborators listed here. Oh, and I'd be remiss not to mention this as well, as we all saw that the FDA granted CG Oncology Fast Track designation and Breakthrough designation recently based upon these data. So, thank you for the opportunity, Dr. Kamat, I appreciate being here today with you on UroToday.

Ashish Kamat: Thanks so much, Mark. Thanks for taking the time and sharing the data with us.

So, Mark, you presented the data, and to be honest with you, I've been part of, obviously, the development of the agents for the last, gosh, more than 10 years, and I was actually surprised, pleasantly surprised, to see single-agent activity as high as you reported, especially based on what you said was the combination with pembrolizumab. Any thoughts or insights into how the single agent you think might be so effective that it's overcoming or surpassing the bar that was set by the other gene therapy, nadofaragene?

Mark Tyson: Yeah, I think it's really ... And that's what I was hopefully careful not to say, is, not sure that we can say that one is necessarily better than the other, obviously, because of the differences in the trials, differences in the populations. But, yeah, monotherapy, I think, blew a lot of people away. A lot of people weren't expecting it'd be so great.

I'm not sure that I can explain that, other than to say that I've seen it in practice with my own patients. I put some real difficult patients on this trial, patients that had CIS for 10 years, and they just kept recurring every three or four months, and they tried everything. And I had put a couple of those on this trial, and a couple of them have reached or have exceeded their 18-month disease assessment, disease-free.

So, part of me wonders, are these single-arm designs, are we not really understanding what the true treatment effect is? If we don't know the counterfactual outcome, are we comparing ... We just get better at treating the disease, and we're not necessarily seeing entirely what the effect of therapy is in a single-arm design, so I don't know if that's playing a part, too. I don't have a good explanation for it, that's the bottom line, except to say that I have seen it in my own practice and I'm pleasantly surprised as well.

Ashish Kamat: Yeah, I think in your response, which was very appropriate, you hit on the key aspects of these study designs, because when we proposed to the FDA the single-arm paradigm, it was clearly in order to stimulate development in this space, because things were just dying out, and companies didn't want to invest in single-arm or in BCG-unresponsive patients. But now that we have a plethora of agents that are being looked at and evaluated, clearly the effect of time migration, better scopes, better understanding, better resection, and the use of blue light, all of that factors in.

So, I'm glad you brought those points up, but I'm still going to put you a little bit on the spot, with the caveat that we can compare across studies. We shouldn't do it. I mean, we can sort of make inferences, and I love your summary slide because it's really going to highlight everything in there. But any insights from your perspective, just given the landscape right now, given what you know about CG, how you might think about sequencing these agents? Let's assume that CG is approved. Let's assume, I mean, that it is approved, and it's available in pembro, and then let's say TAR-200 also gets approved, and QUILT gets approved. Thoughts on how you might select which therapy for what patient at what time?

Mark Tyson: I think a lot of this is going to be patient-driven. And I think that's the great thing about, as you said, all of these drugs that are coming to the market, that patients are going to have so many good options, and I think there's going to be a lot of options before cystectomy. And I think obviously that's the most important thing. There's going to be a lot of things that we can offer before having to remove the bladder.

So, in terms of how I think about sequencing it, obviously right now, nadofaragene is commercially available, and there's a lot of aspects about nadofaragene that are convenient for patients. It's once a day, or once every 90-day dosing. Patients that travel in, that's convenient for them. I know there's some other concepts coming down the pipeline studying nadofaragene as well, and so we'll see if better response rates are observed with combination therapies.

But I don't know that there's a good answer for how to sequence these. Take creto monotherapy, for example, with monotherapy versus combination therapy with pembrolizumab, it may be that a patient looks at the 85% CR rate in CORE-001 and says, "Well, I'll take the 65 or 75% response rate with monotherapy and then advance to combination therapy if I need to, so I can avoid the side effects of pembrolizumab." So, I think it's going to be patient-driven, but I clearly think there's a lot of opportunity for academics to study sequencing and to try to figure out who responds to what and when.

Ashish Kamat: And again, these are really impressive results, and we need to wait for the expanded cohort and the usual caveats that go with it. Any last thoughts on the big elephant in the room, the standard of care right now, Gem/Doce, and how that would factor in with, and we'll focus here just on creto, with creto, the results from creto, and the real-world results from Gem/Doce.

Mark Tyson: Yeah. I still use a lot of Gem/Doce for patients that are not trial eligible and who don't want cystectomy, and it's kind of the de facto standard of care, but it is my last resort. I think that it's hard to compare the really high-quality prospective designs of Steve Boorjian's nadofaragene trial, of BOND-003, of KEYNOTE-057 to retrospective data. And so, I think we have to take those really high and really impressive response rates that we've seen with Gem/Doce, I think, with some healthy perspective on the fact that it's retrospective and not prospective.

So, I think that Gem/Doce is undergoing some really fantastic prospective testing with Max Kates and BRIDGE in the BCG-naive space. And I know that Gem/Doce is a constant, perennial contender as a control arm in any number of designs that are being pitched at the co-op group levels. And so, I am excited to see some prospective data from Gem/Doce, but I'm cautious as it relates to comparing anything that we've seen in the prospective setting to Gem/Doce. I mean, is that way off base?

Ashish Kamat: No, I think you're right, if you look at it from a pure scientific response to a question standpoint. So, what you said is really what I would say as well, or recommend people keep in mind.

But I just think that having real-world data, where it's less controlled, sometimes gives you worse results. Because if you look at any clinical study, whether it's with advanced disease, breast cancer, bladder cancer, the real-world data never matches up to what you see in the clinical trials, because the clinical trials cherry-pick the patients in some way. I'm not saying that they're biased when they cherry-pick the patients, but it's a very strict control. Whereas in the real-world data, you usually see if a drug X has an 80% response rate in the clinical study, it'll drop to 65, 70% in the real world.

So, from that perspective, Gem/Doce, I think, and like you mentioned, the co-operative groups trying to push for having it as a control arm, is very appropriate because it's cost-effective, it's easy for patients to get access to. And of course, we have to factor in the potential huge dollar amounts that are going to be invested in some of these newer agents.

I'm again, just like you, I want to be cautious about the results of a study that's not prospective, but fully recognizing over the last two, three decades we've seen that when something goes from a clinical trial to the clinic, the efficacy drops, so how do we factor that in? And I think control comparisons are absolutely needed to answer that question. So, you are right on target with that response.

Now, Mark, we could spend an hour talking about this topic, but we don't have an hour, so I want to hand the stage back to you. And any closing high-level thoughts you want to leave our audience with?

Mark Tyson: No, I just would like to say thank you for having me. I'm delighted to be here. I'm excited to see BOND-003 mature over time. I think that, like you said, the response rates are really impressive, at least initially. We'll see how that comes out as the second half of the cohort reads out. But just from my personal experience with it, I've been delighted with it, and have seen really good results. So, I'm personally excited as an investigator to see how it all unfolds.

Ashish Kamat: Great. Again, thanks for taking the time and have a happy new year.

Mark Tyson: Likewise. Same to you.