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Ashish Kamat: Hello, and welcome again to UroToday's Bladder Cancer Center for Excellence. I'm Ashish Kamat, professor of Urology Oncology at MD Anderson Cancer Center, and we're joined today again by someone who's familiar to us all, Professor Mark Tyson from the Mayo Clinic. Mark, thank you again for taking the time to spend with us today. Today, we've asked you to spend some time with us talking about CG Oncology, the technology, where the company's headed with its different trials, and to focus a little bit maybe on the PIVOT study. So, thank you again.

Mark Tyson: Thank you for having me, Dr. Kamat. I'm delighted to be here and thank you to UroToday as well for hosting me. Like you said, I'm happy to give an overview of CG Oncology's cretostimogene grenadenorepvec, especially in the context of PIVOT-006, as well as other trials and other concepts in the pipeline. I just want to start by saying I don't have any conflicts of interest with CG Oncology. I'm not an investor, I'm not a consultant, but I am an investigator on VON-003 and a future investigator on PIVOT-006. I'd also like to just take this moment to recognize that PIVOT-006 is really designed and run by Dr. Rob Svatek. He's the brains behind the operation, but I am happy to come at this from the perspective of a co-investigator as well as somebody with experience using cretostimogene.

So, I think it's a good time to pause and just remind our audience of what cretostimogene is. Cretostimogene is a conditionally replicating oncolytic serotype 5 adenovirus that's been designed to replicate in and kill cancer cells. The vector is transcriptionally regulated by a promoter that's upregulated in RB defective tumor cells, and that's present in a lot of different types of cancers. In addition to Creto's restricted replication, it also selectively expresses the transgene for GM-CSF, which is a potent cytokine inducer of inflammation. We have direct tumor lysis and we have an immunotherapeutic effect as the principal mechanisms of action. The primary receptor for Creto is the Coxsackie and adenovirus receptor, which is expressed in all stages of bladder cancer, including low and intermediate risk non-muscle invasive disease. I was asked to provide an overview of CG Oncology, and I'm going to do so in the context of what's already been published, and I think there are four primary studies that are worth considering.

The first was published by James Burke in 2012. A Phase I study involving Creto, 35 patients, showed it was well tolerated, primarily urinary symptoms. Preliminary efficacy data showed a complete response rate of 45.7% with the median duration of response at 8.4 months. If you look into some of the subsets, the multi-dose cohort had a complete response rate of 59.1%, and in the 11 patients that had high RB phosphorylation who also received multiple doses, nine of them achieved a CR for a complete response rate of 81.8%. BOND-II was published by Packiam in 2018, a uro-oncology Phase II trial, 68 patients. In the intention-to-treat population, we saw a complete response rate at six months of 43%, and in the CIS subset, 60%+. CORE1, I think, is where a lot of the buzz is right now. Dr. Roger Li's IIT involving Creto plus pembrolizumab. It's a Phase II, 35 patients. He presented data at AUA last year showing a really impressive response rate, 85% at any time point.

BOND-III, we presented at SUO just a couple of months ago. It was an interim analysis of 116 patients Creto monotherapy in the BCG unresponsive CIS population showing a complete response rate of 75%. So across the board, we see activity in the BCG, high-risk unresponsive population. And so naturally, the company is envisioning taking this product to a few other related spaces. This is a slide I just pulled off the company website just showing where they're at in the development of Creto. And in addition to BOND-III and CORE1, which we talked about already, there is another IIT from Dr. Li involving Creto plus nivolumab in patients who have cisplatin-ineligible muscle invasive disease. There's PIVOT-006, which we're going to talk about later today in the BCG naive intermediate risk space.

And then there's Cretostimogene in the works for BCG-naive high-risk disease, as well as BCG-exposed. So let's talk a moment about the rationale for PIVOT-006. Intermediate risk non-muscle invasive bladder cancer obviously is something that Dr. Kamat has worked quite a bit on in the last decade, but it's a very, very common disease. 30% of newly diagnosed non-muscle invasive bladder cancer patients have this. And they're characterized according to the AUA guidelines by a few different types of histology. So we could see intermediate risk disease with high volume, low-grade TA or low volume, high-grade TA, multiply recurrent low-grade TA, multiple low-grade TA tumors, or low-grade T1. So very heterogeneous population, but they're all characterized roughly by the same pattern of recurrence and progression, mainly a very high risk of recurrence and a very low risk of progression.

It tends to be, as a result, a costly disease because there's a lot of cystoscopies, CT urograms, a lot of cytologies, a lot of repeat TURBTs, risk of anesthesia, and then the quality of life implications associated with all of that. So to the extent that a drug could materially alter the survivorship of patients with intermediate risk non-muscle invasive bladder cancer, that would be a noble goal indeed. So that brings us to PIVOT-006. So PIVOT-006 is a randomized trial evaluating Cretostimogene versus observation. And I just want to take this opportunity to highlight the NCCN guidelines with respect to intermediate risk disease because that observation piece is key. The NCCN guidelines do state the preferred therapy for patients with intermediate risk disease is intravesical therapy. If you sort of look down at the fine print in the NCCN guidelines, that's induction BCG or chemocytobin. Surveillance is of course an option, and that's oftentimes what we choose for patients who are maybe a little older or a little more comorbid or a little less interested in being aggressive.

The AUA guidelines take a slightly different spin on this. The AUA guidelines issue a moderate recommendation for induction chemotherapy or immunotherapy for patients with intermediate risk non-muscle invasive bladder cancer. Moderate recommendation means that the risks are probably outweighed by the benefits, but it is a grade B evidence strength, meaning that future data could possibly change that recommendation. The guidelines are slightly different for maintenance therapy. For newer patients who receive induction chemotherapy, for example, maintenance chemotherapy is a conditional recommendation with a level C strength of evidence. Obviously, that's a little stronger for patients who've received induction BCG, namely the EORTC-30962 trial showing benefit in one year of maintenance, especially in the high-grade histology. So I think that the guidelines do leave room for surveillance here, and I think in practice we oftentimes use it, but there's also potentially a role for intravesical therapy. So this brings us also to PIVOT-006, the study design itself.

Phase three study, like I said earlier, adjuvant Cretostimogene imaging versus TURBT alone for patients with intermediate risk disease. We're going to enroll 426 patients through our two arms, and we're going to talk about the treatment schedule on the next slide. It is an open-label format. The primary endpoint is recurrence-free survival, and low and high-grade histologies are included in that recurrence-free survival endpoint. There are some landmark analyses as well at 12 to 24 months, as well as progression-free survival, which I suspect as we mentioned earlier, will be low. And there's some safety, biomarker, and PRL endpoints as well. The intermediate risk criteria are the classic AUA guideline criteria for intermediate risk. We do have one-to-one randomization stratified according to perioperative chemo, which I think we should all probably be doing based upon SWOG 0337, as well as high and low histology.

And there's an important point to be made here with respect to RMB patients who are not receiving adjuvant Cretostimogene. These patients will be offered crossover opportunity to RMA treatment schedules when they recur, if they recur with the disease that's appropriate for continued therapy on trial. This is my last slide or second to last slide, just showing the administration of the drug. It is an induction course, weekly instillation once a week for six weeks, followed by maintenance at three and six months as well. That's every three weeks maintenance schedule until month nine and 12, it's a single dose. Patients are followed for three years, every three months with cystoscopy and cytology, CTU once a year, and then in that third year, they'll be followed on an every six-month basis.

Just want to pause here. Thank Dr. Rob Svatek and his leadership on this trial, the SUO-CTC and BCAN for their support as well. And like I said, we should be activating this here locally at my site in the next month or two, and I'm very excited to participate. So with that, I'll stop and take questions.

Ashish Kamat: Great. Thanks so much, Mark. As always, a very nice, succinct summary of all the issues related to the trial. In fact, I have to give you credit; that slide that you presented at SUO with the summary, I've used that recently, with your permission of course, in a couple of talks I've given because there's no reason for me to reinvent the wheel, right? So again, really nice presentation here today. I do have a couple of questions about the trial, and then we'll segue into a few things about the technology. And again, full disclosure, I've been involved with helping the company for many, many years with their trial design. And of course, we're going to be a site for their study as well.

So first thing, the question I hear from a lot of people about the study design is the definition of intermediate-risk bladder cancer, because for the most part, most of us, and I'm sure you're in that camp too, think about intermediate-risk disease as being the low-grade recurrent large multifocal tumors, and the high-grade TA tumors we tend to put in the high-risk category, at least mentally. What's your perspective on that, and are you planning to actually include high-grade patients in this study at your center?

Mark Tyson: Firstly, I totally agree. In fact, if you believe the EORTC trial, most of these patients should probably be getting induction BCG followed by one year of maintenance. For the audience, if you peel back the layers on that trial, virtually every high-grade TA patient would qualify according to the scoring system and be eligible for 30962. So, I think it's a really important point. The issue that I think many sites are going to have is BCG availability. And if you don't have BCG available, is this trial a really good alternative? And I think so, probably, and I agree that ideally, we would give them BCG, but in settings where it's not available, I think PIVOT-006 would be a nice alternative for these patients.

Ashish Kamat: I think that's a good point that you bring up for a site that does not have BCG and maybe doesn't have the infrastructure to do GemDoc, by all means, those patients sometimes don't get anything. They get a single dose of chemo anyway, so absolutely, for those patients, this would be appropriate for sure. And again, it's just the nuances of the definition, which I think our audience needs to recognize moving into the actual technology and CG and Cretostimogene and all the different iterations of its name. Over the years, our understanding of how this works has evolved, right? Initially, it was thought there was only an oncolytic agent, then it was thought, well, it's recruiting the appropriate cytokines, then it's the cells, and then it's the T-cells and the killer cells. A little bit for our audience, what's your take on its current understanding, our current understanding of its mechanism?

Mark Tyson: I think at a cellular level, there's two things potentially going on. Just in general, oncolytic adenoviruses like 007 or Creto, like you said, a lot of different names selectively enter the malignant cells, and in this case, the cells that are RB pathway defective, and replicate in those cells, and theoretically only those cells, and cause direct tumor cell lysis. But then there's the transgene expression of GM-CSF, which may also augment this immunotherapy mechanism of action. So, I think that's my understanding of it. I think there's probably both mechanisms going on, and that partly maybe explains why we're starting to see some pretty good response rates in the trials studying the drug.

Ashish Kamat: And lastly, not to put you on the spot per se, but just to pick your brains. With the evolution of what we're understanding with all the other agents that are coming into the field, right, whether it's in the BCG unresponsive space or the intermediate-risk space or the ablative space, there seems to be a lot of different agents targeting certain pathways, targeting certain avenues and aspects and an understanding of the molecular mechanisms of bladder cancer, recurrence, progression, etc. From the slide that you presented, it looks like CG has potentially a role to play in the various different buckets of non-muscle invasive bladder cancer, leaving aside the potential for muscle invasive as well. Do you think that this is going to be something that's truly going to be a game-changer for our patients, pending the results of the studies, of course, but looking at the preliminary data that you have access to?

Mark Tyson: Yes, and the data that I have access to are only data available in the public domain. I have not seen updates to CORE1 or to Bond-III or to CORE2. But absolutely, I think this is going to be a game-changer for patients, and I think it's going to be one of many good options that we're going to have for patients five years from now. And it's not just 007, not just Creto. I think there's a lot, and we're learning a lot about these drugs. We may get to a point where we have trouble sequencing and knowing which drugs to use in whom and when. And so I think there might potentially be a role for other drugs in addition to Cretostimogene, and clearly not everybody's going to respond to Cretostimogene. And it may be that we might start with TAR-210 in patients who have FGFR alterations and Gemcitabine in patients who have DDR mutations.

We might get to a point down the road where we are able to be just a little bit more personalized in our treatment approaches in non-muscle invasive bladder cancer. But to your point, I do think this is a very impressive drug with a very promising future based on what we've seen so far.

Ashish Kamat: Yeah, it's great. And it's great that folks like yourself and Rob, of course, Svatek, and Roger Lee, and the whole list of investigators are so enthusiastic about this technology. Because I think truly, at least looking at the results, and like you said, we're only talking about what's available in the public domain, but looking at what's in the public domain, this looks like it's setting a new bar across the different disease states in non-muscle invasive bladder cancer. So again, congratulations to you. Thank you for taking the time, and it's always a pleasure to chat with you.

Mark Tyson: Thank you for having me, and I really appreciate the opportunity to talk with you today.