Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. We're here at AUA 2022. I'm Ashish Kamat, Professor of Urologic Oncology at the MD Anderson Cancer Center, and it's a distinct pleasure to welcome my esteemed colleague, Dr. Roger Li, who leads pretty much everything to do with bladder cancer nowadays, it seems. Dr. Li at Moffitt Cancer Center in Tampa, Florida. And Roger, it's great to have you here.

Roger Li: Thank you so much, Dr. Kamat. And again, thanks so much for that kind introduction. And none of this would've been possible without your mentorship. So I truly, from the bottom of my heart, thank you very much.

Ashish Kamat: Oh, you're more than welcome. I just open doors, and then you can do great things. Right? So speaking of great things, you're doing a lot of great things.

Roger Li: Thank you.

Ashish Kamat: And there's a lot of stuff that you're involved with here at the AUA, and I'm sure we hear a lot about that in some of our other sessions, with UroToday, and at the AUA itself. But today, right now, here, what I want to ask you about is your work with CG0070, and the trials that are ongoing, including those that you're presenting here at the AUA. So if you could just share with us, what's going on?

Roger Li: Sure. So we'll start from the very beginning. So CG0070 is an adenovirus vector that is thought to act through a dual-pronged attack, and it lices the cancer cells. In doing so, it releases the tumor-associated antigens into the microenvironment, and elicits a cancer-specific immune attack.

So, this drug was originally developed in the 2000's actually. Long time ago. And the first phase one trial was conducted and reported in 2012. And that showed the pharmacokinetics, and pharmacodynamics, to support the use of an induction course of six weeks, followed by three weekly maintenances at months three, six, essentially reproducing what we do with BCG. And so, based on that, there was a phase two follow-up study, that showed a complete response rate of about 65% or so. And a 12-month complete response rate of about 28%. So based off of that, and of course, as you know, immune checkpoint blockade has been approved in the BCG unresponsive setting. We hypothesize that the oncolytic virus can have mechanistic synergism, with immune checkpoint blockade, and are testing this in the BCG unresponsive setting.

And we're really seeing some very exciting, preliminary results. So, in the first 22 patients, and we're going to be presenting this data at the AUA this time. In the first 22 patients, we're seeing 20 of them having a complete response seen at three months. And out of all of the patients, the eight patients that have reached the 12-month mark, six out of those eight patients continue to have a complete response. So I truly think that we are on the tip of something special, and that's going to be a game changer in the BCG unresponsive setting.

Ashish Kamat: Yeah. I mean, these numbers are, in some ways, almost too good to be true, right? I mean, they're so good that if this goes on, and you can see this in a larger cohort of patients, even if you lose 15, 20% response rates, I mean, this is really going to change the response bars that we are seeing, because KEYNOTE-057, nadofaragene, the 12 months, the same 25, 23, 28% that you saw with single agent CG0070.

Do you think the combination is where we are headed? Any thoughts about the single agent, and the work that's going on with just the single agent?

Roger Li: For sure. So I should have also mentioned that there is an ongoing registration trial for the monotherapy, and that's called the BOND3 Trial. It's kind of a little play on the CG0070 naming of the oncolytic virus. And that trial is aiming to accrue about 110 patients, and it's ongoing. Accrual is going well. So we're still waiting to see what the results that are going to be coming out of that trial is going to look like.

But back to your question about the combination. I do think that we have tested both agents individually, by themselves, and neither can reach the mark that we're seeing with the combination. So that really speaks to the mechanism of the two agents.

And I've taken a deep dive into the basic signs behind how oncolytic virus work, and truly the immunogenic cell death that's elicited by the oncolytic virus. And in this case, CG0070 also has a GMCSF trans gene that induces the recruitment of antigen-presenting cells. So all of those added together, I feel that it brings in all the T-lymphocytes into the tumor microenvironment. And then you have the immune checkpoint to be added onto that. It really is a killer one-two combo.

Ashish Kamat: Yeah, no. So let me ask you a kind of a logistic, philosophical question. If you're having this combination, that's working really well, and obviously, we have data from pembro alone, and now data from the BOND3 study, what do you think is going to be the strategy for the combination, as far as registration's concerned?

Roger Li: That's a great question. And we've thought about it, a little bit, and are reaching out to several different agencies, including the SUOCTC, to see whether we can get support for the next upcoming trial. So the design that we have in mind is, with a randomized controlled setting, testing the combination against pembro by itself.

Now, of course, with pembrolizumab, as you know, the CR rate at three months even is modest at best, I would say. And also coupled with the cost and the toxicity that we're seeing for the pembro, there are a lot of urologists that are very hesitant, and probably a lot of patients who would be hesitant on enrolling onto that trial as well.

So, the backdoor mechanism that we came up with is, if you were to fail on pembro single arm, you have the option of being switched to the combination arm, to see if the combination can actually work in the post-pembro setting. So again, that concept is being discussed. Whether it's going to come out exactly like that, it's still to be seen, but I'm very excited to see not only the design of that trial, but also the results, hopefully in the near future.

Ashish Kamat: Right. Yeah. Maybe you brought up the question of urologists being hesitant to use treatment that may not be as effective for the patients. Urologists also tend to be a little hesitant using an agent that's systemic, because of the perceived toxicity, being something that's hard to handle. Could you share with us your experience from the trial, the combination? So what's the toxicity profile, and any pearls for people that might be thinking of enrolling in the larger studies?

Roger Li: Sure. Be happy to. So in the current trial that we have ongoing, albeit there's still only a small subset of patients who've been treated. At Moffitt, we are the leading site for that trial accrual. So I probably have the most experience with the combination. And I would say that it's fairly well tolerated, by the patients in this cohort at least. Most of the symptoms are related to bladder symptoms, as like BCG, and other CG0070 trials.

From a systemic standpoint, we really haven't seen that many SAEs. Immune-related SAEs, we've only seen a couple with autoimmune thyroiditis, that's presumably brought on by the immune checkpoint blockade. But in terms of the systemic therapy-induced severe adverse events, we haven't really seen that much that we're seeing, for example, in the metastatic setting. And I think that may have to do with the tumor burden that the patients have, where the immune checkpoint blockade may not elicit as severe of a reaction, in this patient population.

Ashish Kamat: It could also just be a function of the number of patients in the study, right? Because KEYNOTE-057 was also non-metastatic patients, but the side effect profile kind of fit in with the reference for pembrolizumab. So maybe, when there's a larger cohort of patients, you will start to see-

Roger Li: Absolutely.

Ashish Kamat: The expected side effect profile. But at least it's encouraging that there's not an additive side effect profile, from combining the two drugs, which is great.

Roger Li: You're absolutely right.

Ashish Kamat: So again, it's a pleasure to chat with you. We could chat forever. But in closing, if you just want to leave our audience with the highlights from what you're going to be presenting.

Roger Li: Sure. So from the CORE1 trial, that we're going to be presenting on Monday, we're presenting the preliminary results, showing that 91% complete response at three months, and that 75% complete response at 12 months. I'm also going to be talking a little bit about the correlatives that we're doing from a CORE2 trial, which is using a similar concept of CG0070, six doses intravesically, plus two doses of nivolumab, given in the neoadjuvant setting, for patients with cis ineligible muscle-invasive bladder cancer.

We're seeing some really exciting preliminary results there. Although I can't share that currently, because it's under embargo from the ASCO. But from the correlative studies, what we're finding is that the combination actually works, even in those patients with negative PD-L1 baseline tumors. And what that suggests to us is that the oncolytic virus may actually be inducing the immune response, that's then added on by the immune checkpoint blockade. And as you know, that phenomenon hasn't really been described previously in the [inaudible] of an IO setting. So also very excited about that.

The final trial that I wanted to bring up is another trial with the monotherapy, that we're envisioning using in the intermediate risk, non-muscle invasive bladder cancer cohort, in the form of a marker lesion trial. So we're working on that, and hopefully, it's going to be forthcoming in the near future. But overall, I can't just overstate my excitement about these series of clinical trials. And hopefully, we'll be able to bring oncolytic virus to our bladder cancer patients and be able to help them keep their bladders, and live longer.

Ashish Kamat: Yeah, no, I mean, this is great work, and it's exciting times for us in the bladder cancer community, to be seeing the kind of work that you're doing. So keep it up.

Roger Li: Thank you so much.