Ashish Kamat: Hello everyone and welcome to Uro Today'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 once again doctors Roger Li and Trinity Bivalacqua, who really have been frequent guests on this forum sharing their insights, their ideas, and thought processes with all things related to bladder cancer.

Today we have the privilege of having both of them here to discuss the data that was just presented at ASCO regarding the CORE-001 study. And with that, Roger, I'll let you take it away.

Roger Li: Thanks Ashish. So at ASCO we presented the final results of CORE-001, which is a phase-2, single-arm study of cretostimogene grenadenorepvec in combination with pembrolizumab in patients with BCG-unresponsive CIS. So as everybody has probably been familiarized with already, cretostimogene is an oncolytic immunotherapy that is conditionally replicating in RB defective cancer cells, and at the same time encodes a GM-CSF pathway. In previous studies, cretostimogene has been tested as a monotherapy in BCG-exposed as well as BCG-unresponsive patients. And in the most recent update presented at AUA, the overall response rate seen with creto monotherapy in the BCG-unresponsive CIS setting was 75%.

So we really hypothesized that there is mechanistic synergism between creto and pembro, and thus tested it in the BCG-unresponsive CIS setting using exactly the same administration protocol as on the monotherapy trial, but adding to it pembrolizumab given IV every six weeks. The primary endpoint for the study was really designed around what we know about pembro monotherapy, which resulted in a 12-month complete response rate of around 19%. And that was set as the null hypothesis for the primary endpoint of the CR at 12 months.

And so from the final cohort, we see that in a very strict intention-to-treat population, there was seen to be just under 83% complete response at any time. At 12 months, it was 57.1%, and at 24 months, 54.3%. Again, in the strict intention-to-treat population. And if using Kaplan-Meier estimates, the 12-month and the 24-month landmark survivals are even better.

What's unique about this combination is that it has really great durability. And as we can see here, the 12-month landmark durability was over 80%. And even at 24 months, over 70%. It's important to point out that no patient on this trial had actually progressed to either muscle-invasive disease or metastatic disease, and that's including all of the patients who had undergone a radical cystectomy.

The AE profile for the combination treatments was very similar to what's been reported for the monotherapy trials in the past, with grade 3 SAEs noted in 14.3% of the patients overall. And as you can see, the vast majority of the AEs were related to grade 1 or 2 bladder-related symptoms.

So with that, I'd like to thank all of the key collaborators that helped us put this together, the study coordinators, and the nurses. And lastly, but not least, all of the patients and their family members who participated in this study. I'd also like to mention that the study has been simultaneously accepted for publication at Nature Medicine and you can find the overall details of the study there. Thanks.

Ashish Kamat: Thanks so much, Roger, and congratulations on presenting this data at ASCO; clearly a national stage and not often that we see non-muscle invasive bladder cancer featured at ASCO, and I think it's kudos to not just you but all the investigators and all the companies that have come out and put their dollars and their resources and essentially helping our patients, right?

Trinity, let me flip it over to you here. And at a high level, what are your thoughts when you see this data being presented with the background of all the information you have in general with all the work that you've done in NMIBC over the years?

Trinity Bivalacqua: Yeah, I think Roger pointed to really the most remarkable point, the remarkable aspect of this trial is that the tail in the Kaplan-Meier, or the durability in those patients that had a CR is remarkable, something that we typically don't see in these types of trials. So this combination therapy clearly has efficacy in preventing recurrent disease in a very high-risk group of patients.

Lastly, the mechanism of action and how these two agents, when combined together, is causing this effect. That I think is really up for discussion and if we could figure that out, I think it'll actually help us design other trials as well as other therapeutic approaches for the treatment of this disease. As Roger pointed out, very few patients progressed and that's also important. Obviously as a clinician in taking care of my patients, I don't want to see that, right? We don't want to see these patients progressing and that did not occur with this. And I think Roger deserves all the credit. He was one of the biggest advocates for this combination therapy from the beginning. So kudos to him as well as all of CG Oncology for getting this done.

Ashish Kamat: Yeah, great points. And again, when we talk about the tail and the benefit of adding immunotherapy on there, Roger, in your opinion, obviously there is no additive toxicity as you mentioned, but based on what you presented and the efficacy of monotherapy, as you mentioned and contrasted in there with the data that was presented earlier this year at AUA, what's your sense as to whether this is something you would think about applying to all patients who want to get CG or would you select out a group of patients? I know that's not something you can tease out from your data from the study, but just with your experience that you've amassed in this field.

Roger Li: Yeah, I think certainly the most impressive aspects of these results were the durability and also the lack of progression. And I think certainly we've been focusing in on the three-month complete response rates and the durability of responses per the FDA guidance. But now I think we have a few treatment regimens at our disposal for these patients in a bladder-sparing way. We really have to look at the long-term response rates that determine: what is the efficacy level that's worthwhile for the toxicity that's incurred by the treatment?

And I think overall, certainly if you look at the PD-1 or PDL-1 inhibitor monotherapies, the risk-to-benefit ratio is underwhelming at best. But I think when you present a treatment option to the patient where you're giving them a more than 50%, in actuality probably even higher than that chance of successfully sparing their bladder, potentially looking at a cure for BCG-unresponsive disease, with the trade-off being only a 14.3% SAE rate, many of which were just laboratory values and not clinically significant. I think that's when patients are really going to decide that the efficacy of the treatment is really worth the risks. And I think that's what we have to look for in the future.

Ashish Kamat: Yeah, that's a great point to raise. And you are in the unique position, and I say you as in I mean all the investigators with CG, of having two trials reading out almost at the same time, one with a single agent and one with a single agent plus combination, right? Which is unusual. Normally we have one drug or the combo reported out and that's what we get. So here it's almost like we have two efforts coming out simultaneously, clearly very good results with CORE-001, but with the BOND study, too, you're seeing very good results as well. So it's almost like we have too many choices, which is never a problem, right?

Talk to me a little bit about the CR rate that you just mentioned, because when you talk about intent to treat and then the Kaplan-Meier, as you've alluded to, and Trinity, you've been saying this for a while too, patients don't care what happens at three months. They actually care what happens at 12 months, 24 months. So I know Kaplan-Meier estimates are sometimes to be taken with a big grain of salt, but Trinity, when you look at this and you look at the ITT and then you look at the actual duration of response, what's your gestalt as to where this will mature at the 12 and 24-month disease-free survival for our patients?

Trinity Bivalacqua: Yeah, I think in this trial, I think we do have to acknowledge that this is a small trial; that it's a phase 2, 35 patients, and the results are striking. And I actually think in this small trial we're going to see that those Kaplan-Meier estimates, as you pointed out, are probably going to be pretty close to what it estimated it to be because it's such a small trial.

I think the results of the next trial, which is obviously a larger trial, are going to be more informative for us. But right now, I think with what we're seeing in this 35-patient trial, I do expect it to be durable. And I think one of the reasons why we might be seeing this durability is that remember, in these trials we allow for re-induction in patients that don't respond at that early time point, which I think is also a novel trial design as it relates to other trials in the field. So maybe that's contributing to some of the durability when combined with PD-1 inhibitor. It's unknown at this point.

Ashish Kamat: And I think people will often bring up the question of re-induction for patients as though it's a negative. I think it's a positive. I think it's something we've learned over the years that it's not unsafe for our patients to get another course of drug X, and why not the same drug that they've currently been exposed to, especially if it's an immunotherapy. So we've learned this and I think it's a strength of the study design rather than a detraction from the study design that we've learned and we've adapted and moved forward after the FDA guidance document.

Roger, I'll give you the last word. What are some of the high-level messages that you want the audience to take home from, not only your presentation at ASCO but also the publication that's coming out?

Roger Li: Yeah, thanks, Ashish. So I think from both the CORE-001 and also the BOND-003 study, we're seeing excellent response rates in the short term with creto being kind of the backbone of the therapy. And that really points to its mechanism of action. But the durability that we're seeing on CORE-001 I think is unprecedented compared to any of the studies in the past. And it really allows patients a real choice now to choose a therapy that can, for the long term, help them preserve their bladders. And I think going forward, we really have to choose up front to select for patients who may be fit for the combination versus the monotherapy, or maybe even after trying the monotherapy, if they have signs or molecular signatures that demonstrate a non-response to the monotherapy, they can then be switched over to the combination. But overall, with so many different combinations, as you alluded to earlier, it's really an embarrassment of riches at this point. But such exciting times for us investigators, but more importantly for our patients.

Ashish Kamat: Yeah. Great points as always, and again, I want to congratulate you and also you, Trinity. This is excellent. Thank you so much for all the work you're doing, and thank you to Uro Today for allowing us to feature this.

Roger Li: And you as well, Ashish. This study wouldn't have been possible without your input, so thank you.