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Sam Chang: Hello, my name is Sam Chang. I'm a urologist in Nashville, Tennessee at Vanderbilt University Medical Center, and we are quite fortunate to have Dr. Neal Shore. Dr. Shore is the medical director at Carolina Urologic Research Center and he really needs no introduction. His influence and his research contributions in all urologic cancers have been so significant over the years. We have the opportunity for Dr. Shore to give us an update and an evaluation of the KEYNOTE-676 trial, which looks at Pembrolizumab and a special cohort of patients. So, Neal, thank you so much for being here today and going over this study with us, and we look forward to what you have to share with us today.

Neal Shore: Well, thank you, Sam. I look forward to it. I'm really honored to be on the program today with you. And congratulations on this really well-deserved award, the Hugh Hampton Young. I think it was richly and appropriately deserved. Congratulations to you and thank you for having me today.

Sam Chang: Thanks very much, Neal.

Neal Shore: It was a real pleasure to present this at the Trials in Progress Session at the AUA 2024 in San Antonio. I'm so happy to be able to present it again and discuss it with you, Sam. You can see all the co-authors here. This is a global study and this is really sort of a bit of an offshoot of a larger trial looking at BCG plus Pembrolizumab versus BCG induction maintenance in BCG-naive patients. This particular Cohort A that we're looking at now, and similarly to other immunologic trials that are phase 3, is trying to understand that by adding a checkpoint inhibitor, a PD blocker such as Pembrolizumab, in conjunction with BCG induction and maintenance, can that augment the good results that we already see with BCG induction and maintenance? But particularly, cohort A is a little bit different. Now I'm going to go into that.

Everybody knows the incredible benefit from Professor Morales, who taught us all about the use of BCG, and we've been using it. It's been the gold standard. But there are challenges with production and shortages, and clearly, it's not 100% effective so we do see patients who have persistence and recurrence. We've recognized early on that PD-L1 expression is a correlate of bladder cancer biology, and so there can be an attenuation of responses to BCG by repressing activated T cells. And thus, KEYNOTE-057, which I had the pleasure of being part of and I know you were as well, Sam, that was really the first time we were able to demonstrate that in the BCG-unresponsive carcinoma in situ patients, true unresponsive, the five plus two or the two inductions, that patients could benefit and get complete response rates with Pembrolizumab.

So we know that there's a good overall tolerability and safety profile. That said, one needs to be cognizant of immune-related adverse events, really since checkpoint inhibitors came into fruition across all tumor types, really starting back about eight years ago and certainly in bladder cancer. We see it now in kidney cancer and even in the tumor agnostic indication for MSI-H in prostate cancer.

So here is cohort A of the KEYNOTE-676. I already told you about the BCG-naïve comparing Pembro and BCG versus the monotherapy induction and maintenance. What's interesting here is these are patients who had previously received an induction course of BCG, but no maintenance. And they could have received their BCG between zero and six months of the recurrence, six to 12 months, or a year to two years. And so this is actually a very large population of patients who get, for lack of a better term, the less than adequate amount of BCG. So we're doing well with the accrual. It's a global study. The primary endpoint is a complete response rate.

Again, in patients with CIS, you see the secondary endpoints listed here and, of course, we'll follow these patients for safety and survival. So it's ongoing. It's a pleasure to be part of this. I'm involved with two other important BCG-naïve IO combination trials. I'm excited about this. We've had such an explosion of other therapies as well, and I think for our colleagues listening right now, NMIBC, whether it's BCG-naïve or BCG-less than adequate or BCG-unresponsive, a lot of great data is going to come forward in the foreseeable short term, so thanks.

Sam Chang: Neal, thank you so much for that presentation. How is enrollment going? We've got so many trials going on. How are we doing with institution sites and the number of patients enrolled?

Neal Shore: Yeah, we're doing well. I mean, it's always interesting, Sam. It's a great question. I love doing clinical trials. To me, my mantra has always been, 'You're a clinical trial patient until proven otherwise.' That's the sort of theme we've tried to really get, which is the academic model in the community, to have enough good quality trials, early phase, phase 3 in GU oncology. It's sort of very similar to our colleagues in the UK and Switzerland who run the STAMPEDE. They really basically say and try to encourage that you're a clinical trial patient until proven otherwise, and that's how we change clinical practice. As you can see, this is a global trial. There are some sites in the world that are pretty amazing in their abilities to enroll. And then there are other sites where everybody will say, "I've got the scale. I see these patients." And I think you and I, and many others, are continuing to try to get people to develop their clinical trial bonafides. So there's a little bit of a seesawing effect, but I'm confident we will finish accrual within the year.

Sam Chang: Oh, that's fantastic. As you look at the landscape with the IO therapies and the intravascular therapies and the combination, let's get your crystal ball out and consider these. It just seems to me that a combination of therapies is more likely to win out versus a monotherapy, so I'd love to know your thoughts about that.

Neal Shore: Yeah. Well, it certainly really depends, as you know, on the stage. And there's heterogeneity, we use that word a lot with prostate cancer. There's a lot of heterogeneity in bladder cancer and we need better biomarkers and maybe artificial intelligence will help us with who's going to be a BCG responder and who won't be a BCG responder. AI may help with that. I know there's work that we're doing on that, I'm sure you are too, and other potential biomarkers, molecular tumor markers, and that'll really help us. Ultimately, that gives us a sort of personalized or precision approach. I think for some patients who have really the variant histology, as opposed to just the pure transitional cell, there's probably, assuredly going to be a role for combination therapy. So I think that it's a great question. We continue to try and learn so that we can ultimately individualize, not intensify when there's no need to, but then intensify for the patients who have more aggressive disease.

Sam Chang: Yeah, Neal, I think that's a really key point regarding one of the things that we, I think, discuss daily is that accurate identification, risk stratification, and then trying to come up with more precise therapies. Just as you say, deescalate versus escalate, decrease the intensity of surveillance versus, "These are the patients who really need upfront aggressive therapy," perhaps combined therapies, just as you mentioned. And so we look forward to the read-out of this trial and many of the others that you're helping to lead. So thanks so much for spending some time with us.

Neal Shore: Well, my pleasure. Thank you.