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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are live at the 2024 ASCO annual meeting. I'm delighted to be joined today by Dr. Roger Li, a urologic oncologist at the Moffitt Cancer Center. Roger, thanks so much for joining us today.

Roger Li: Thanks for having me.

Zach Klaassen: It's always great having you on. We're going to talk about some cool data today, CORE-001. You're presenting data at ASCO. Just tell us a little bit of background before we get into CORE-001 about the unmet need for BCG-unresponsive non-muscle invasive bladder cancer.

Roger Li: Yeah, absolutely. As you know, the BCG-unresponsive disease space has been really hot over the last few years because it's really an unmet need in this clinical space where patients are older and frail. As you know, the standard of care is radical cystectomy. Some patients cannot even undergo such a morbid procedure, others refuse. So we need to have effective bladder-sparing therapy options for these patients, not only to prevent recurrences but also to prevent the progression of the disease as well. So hence, there is an explosion, I would say, of clinical trials and data emerging from this disease space and drugs that are approved by the FDA. There are three now, so very exciting times.

Zach Klaassen: Yeah, it's great. It's funny, I tell my residents it's almost like non-muscle invasive bladder cancer is what prostate was 5 years ago.

Roger Li: Absolutely.

Zach Klaassen: It's a great space to be in right now and it's really given us options for our patients. And so that kind of leads to cretostimogene. Maybe give us a little background on the mechanism of action, maybe some of the early data that's been published already.

Roger Li: Sure. So, cretostimogene grenadenorepvec...

Zach Klaassen: Glad you're saying that, not me. That's perfect.

Roger Li: ...is an oncolytic immunotherapy. It's a viral therapy that is infused directly into the bladder. The oncolytic virus is unique in that it has an E2F driver. So it requires free E2F molecules, which are only present in Rb-defective cancer cells, for it to bind to the viral promoter, thus causing viral replication. In addition to that, it also has a GM-CSF transgene, and GM-CSF, as you know, is a cytokine that is a systemic immunostimulant. So it boosts the oncolytic immunotherapy therapeutic effects of the virus. So it really has a two-pronged attack where it not only lyses the cancer cells specifically, but also uses the lysis of the cancer cells to generate neoantigens to generate an adaptive immune response.

Zach Klaassen: That's a great breakdown. Let's swing to CORE-001. Give us a little background on how this trial maybe came to be and the study design that you guys came up with.

Roger Li: Absolutely. So as you know, pembrolizumab is already approved in the BCG-unresponsive CIS setting with a complete response rate of 41% or so at 3 months and 19% at 12 months. So Creto has also been looked at as a monotherapeutic agent, both in phase I through III trials now. In the phase II trial that was reported out a few years back, Creto achieved a 65% complete response rate in patients who were exposed to BCG, and long-term, 12 months, it was 25% or so. As you know, also presented by Dr. Mark Tyson recently at the AUA, the most recent data from BOND3 showed a 75% complete response rate with oncolytic virus alone, monotherapy in the BCG-unresponsive CIS setting.

So we really thought that the mechanisms of action of the two drugs, Creto and Pembro, were very synergistic, where the Creto actually generates a lot of the cell lysis, creates this localized immune response, and then you bring in the Pembro to really boost the immune response that's specifically anti-cancer. So we thought that the combination would actually work even better. And so that was the genesis of the trial. We designed it as a single-arm study, as any of the other studies in this disease setting, and the primary endpoint, we actually looked at the 12-month CR rate, knowing that Pembro's 12-month CR rate, as mentioned, was 19%. So we set that as the null hypothesis, and as long as we see 35-36% or so complete response with the combo, then we'll deem this phase II study a positive trial to move it forward.

Zach Klaassen: That's great. So how many patients, and tell us some of the key results that you guys had in your trial.

Roger Li: Yeah, I'd be happy to. In total, we enrolled 35 patients, all with the BCG-unresponsive CISs per the 2018 FDA guidance paper. These patients were treated with the cretostimogene as per the BOND3 protocol and pembrolizumab every 6 weeks IV for up to 2 years. What we observed, the primary endpoint at 12 months, we're seeing a 57% complete response. That's in the intention-to-treat population. So there were several patients who didn't have any disease recurrence but fell out for other reasons that we still included in the denominator to arrive at that number.

Zach Klaassen: That's great.

Roger Li: At any time, we're seeing just under 83%. What's even more exciting is that even out to 2 years, we're seeing 54%. Out of all of the patients who responded at 1 year, pretty much everybody continued to respond at 2 years, and I can tell you from personal experience that there were a couple of my own patients who've come in for their third-year checkups now that continue to have this response. So are we looking at actually a cure of BCG-unresponsive CIS? That remains to be seen. We'd like to follow these patients out even longer, but I'm very excited about the data.

Zach Klaassen: But even in the last couple of years, that would have been a pipe dream.

Roger Li: Absolutely.

Zach Klaassen: Now we're seeing a possibility of that, which for these patients, as you mentioned, too sick for cystectomy or refuse, have a phenotype of a disease that is potentially going to progress and we maybe have a cure with a combo therapy.

Roger Li: Absolutely. And again, what's exciting is the durability. We're seeing an 82% duration of response in those responders at 12 months. In addition to that, if you kick out the patients who fell off for reasons other than disease recurrence, the landmark high-grade recurrence-free survival at around 1 year is 77%, and at 2 years it's 70%. So very, very high numbers that we didn't even dream of a couple of years ago. And I think it really kind of speaks to the mechanism of action of the combo. The other thing that I wanted to bring up also is that there was no patient on the trial that actually had progressive disease.

Zach Klaassen: That's great.

Roger Li: And I think that's something that's probably understated in previous studies because I truly believe that the primary goal for treating patients with BCG-unresponsive disease is to prevent them from progressing to muscle invasion and metastatic disease so you actually miss the window of opportunity for a cure. And with this, the median follow-up now is out to more than 2 years.

Zach Klaassen: That's great.

Roger Li: In the patients who've undergone radical cystectomy because of disease recurrence, we're not seeing that. In the patients that continue to be treated, we're not seeing that. So that's really remarkable.

Zach Klaassen: That's exciting. I want to come back to the 12 and 24-month data in a second, but maybe just talk about tolerability. Obviously, we're combining systemic therapy with a local therapy. Did you guys see any new signals? Was it well tolerated?

Roger Li: Yeah, it was very much as expected from what we know from the monotherapy trials with both Pembro alone and cretostimogene alone. With Creto, it's mainly bladder-related symptoms. With Pembro, as you would imagine, it's some of the immune-related AEs. That's not happening at any higher rate than what we've observed in the past in KEYNOTE-057, for instance.

Zach Klaassen: That's great. So at the risk of comparing trial side-by-side, which we're not supposed to do, but we're going to do because we're having a conversation, if you look at the 12-month data from CORE-001 and the 24-month, how does that stack up to some of the other FDA-approved regimens that we have?

Roger Li: No, I think when you run trials in such a similar disease population, you're bound to compare.

Zach Klaassen: It's easy to do it.

Roger Li: So of the three drugs that have been approved—pembrolizumab, nadofaragene, and also Anktiva—I think, certainly, the complete response rate that we're seeing at three months for Pembro is 41%, out to 12 months it's 19%, out to 2 years it's down to about 9%. So kind of comparing against that, there probably is some mechanistic synergism between the virus and the Pembro. With nadofaragene, we know that initially it's about 55% or so, and it drops down to 25% at 1 year, and out to 2 years, Vikram Narayan from Emory just published the 5-year follow-up data, it's down to 20% or so. Anktiva just got approved. From the press release by the company, at least, the final set was on 77 patients with an overall response of around 60-65% or so. At 1 year it drops down to 36%, and then at 2 years down to 25% or so.

So I think what is clear from all of the approved products is that long-term, at least, there's still not a great solution for helping patients to keep the disease away. I think with the combination of Creto and Pembro, really, for the first time, in my opinion, we're looking at a viable option to offer patients to really be able to cure them of their disease.

Zach Klaassen: That's great. So what comes next for the combo? Obviously, we've got the phase II trial, 35 patients. What's the next step for the combination?

Roger Li: Yeah, so obviously BOND3 results also look very promising, at least the preliminary data. So it's up to us to figure out who we need to treat with the combo because it does still add toxicity, and who we can treat with the monotherapy alone. And more importantly, in my opinion, for those patients who fail or for the disease that recurs after initial treatment with either Pembro or Creto, does the combination add more benefit in that setting? So certainly the CG Oncology is planning on such studies. We're also going to be looking at urine biomarkers in the future to see whether we can use that to predict response to the monotherapy, for instance, to move patients onto combination therapy a little bit sooner, but very, very exciting times.

Zach Klaassen: Yeah, it's great data, great conversation. Just for our listeners, a couple of take-home messages from our great conversation today.

Roger Li: Yeah, I think for the first time, again, we're potentially looking at a cure that's safe, that prevents the cancer from progressing out of the window of curability, and also it's well tolerated in line with what we know from previous monotherapy trials, no synergistic toxicity signals. But more importantly, I think we're truly at a very exciting time, as you mentioned, with bladder cancer with so many different options that we have at our disposal. It's really up to us now as urologists to figure out how to sequence these, for which patient we offer the right option, and how to maybe use some combinations in certain instances. It'll be fun times.

Zach Klaassen: It'll be fun times. Always good chatting with you, Roger. Thanks for your time and expertise today.

Roger Li: Thanks so much.

Zach Klaassen: Thanks.