Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston. And I'm joined today by Dr. Roger Li, who is Assistant Member of GU Oncology at Moffitt Cancer Center and the lead author on the gene therapy talk that was recently presented and also the study that is ongoing.

Roger is well known. He's done a lot of work in bladder cancer and is currently focused on developing novel therapies, especially in patients who have high-grade recurrences after BCG. Dr. Li's going to talk to us today about gene therapy in general, and then we'll have a quick Q and A session at the end. So with that, Roger, the stage is yours.

Roger Li: Thanks so much Ashish for that kind introduction. So we're going to go ahead and talk a little bit about gene therapy for the non-muscle invasive setting today, and there are my discloses. So just as an introduction, a lot of the audience for this talk will already know BCG-unresponsive non-muscle invasive bladder cancer have a significant risk of disease progression. Radical cystectomy currently remains the gold standard treatment for the setting. However, as we know it's associated with a high perioperative morbidity rate, and many patients are unwilling or ineligible to undergo the procedure. Hence, conservative management strategies are critically needed in this disease space.

So really the story begins with pembro with the KEYNOTE-057 trial, in which about 100 patients or so that were accrued in 54 sites underwent pembrolizumab treatment every three weeks for up to 24 months or disease recurrence. And what the authors found was that at three months evaluation about 41% of the patients were completely free of disease recurrence. And they did also find that this response was somewhat durable. So 18 out of the 39 patients who did have response had a durable response at 12 months, making that about 19 to 20% of the overall cohort. And in addition to that, the toxicity for this treatment was manageable with only 13% of the patients having Grade 3 to 4 AEs.

And as a result of this trial, the FDA was able to approve the use of pembrolizumab for BCG-unresponsive patients in January of 2020. So almost two years ago now, seems like time flies. And in the backdrop of that, there has been currently an interest in looking into the efficacy of gene therapy trials to hopefully try to reduce the toxicity of the treatment, but also to increase the efficacy of the treatment. And so the story there really starts with Adstiladrin or nadofaragene firadenovec, which is a recombinant adenovirus vector that's replication-deficient. And it essentially knocks in an interferon-alpha gene into the urothelial cells.

So both the benign and also the cancer cells. Making the urothelial cells a factory for interferon-alpha for bladder cancer. And in a Phase 2 trial that was published in 2017, the six-month complete response rate was 44% and the 12-month recurrence-free survival rate was 35%. And that lended the rationale for a Phase 3 study, which was subsequently conducted through the SUOCTC. And that was reported in 2020 that found a complete response rate of over 50% at three months. And in the CIS containing patient cohort and also a higher efficacy rate in the pathway only cohort.

And in addition to that at the 12-month mark, a 24.3% complete response rate was observed in the CIS containing cohort. So somewhat better than the efficacy of pembrolizumab and the adjudication on the approval of this drug agent by the FDA is still pending. But the other thing is unlike the pembrolizumab, the toxicity that was seen with Adstiladrin treatment in this trial was actually much better. So with very few Grade 3 adverse events seen. And most of the adverse events that we're seeing were basically related to bladder-related symptoms.

So in the backdrop of that, we were also very interested in looking at the efficacy of CG0070, which is an engineered adenovirus vector with E2F promoter and also GM-CSF transgene. And what this does is it specifically limits the replication of the viral vector only in the cancer cells that are Rb-pathway deficient. So in these cells, the Rb is either not available because of phosphorylation or they're simply just not expressed. And due to this, the E2F is then freed up to bind the promoter of the virus, and that leads to the replication of the virus and that leads to viral propagation and cancer kill.

And the CG0070 is really purported to work through a two-pronged attack first by [inaudible] the cancer cells. And also in addition to that, causing a tumor-associated immune response. So through both of these mechanisms control the tumor. In addition to that, DDM is also used to remove the GAG layer within the bladder so that the adenovirus vector can have access to the bladder cancer cells to enable cancer kill and maximize cancer kill. So here's really the workflow for the treatment. So the patients come into the clinic, the infusion clinic, they will have a three-way catheter inserted, and the bladder is first washed with a normal saline wash followed by a DDM wash and a second saline wash. And finally, the CG product is infused for about 45 to 60 minutes for total treatment time of around two to three hours.

In the couple of studies that have been conducted using CG0070 as a monotherapy in the past, it's been shown to have both safety and preliminary efficacy, especially in the CIS containing cohort with a complete response rate there at any time around 46% in the Phase 1 trial, up to 65% in the Phase 2 trial, and the CR at 12 months was found to be about 28%. So based on those really encouraging preliminary data, we launched a Phase 2 study combining CG0070 with pembrolizumab in the BCG-unresponsive setting.

And this trial is multinational as well as multi-centered and rolling up to 35 patients in a single-arm fashion combining CG0070 plus IV pembro, where CG is given according to its original administration schedule of weekly times six induction courses followed by maintenance courses given three weekly, every three months in year one and every six months in year two, and pembro is given every six weeks through year two. So the primary endpoint for this study is complete response rate at the 12-month mark. And that's by both cystoscopy and also random bladder biopsy performed at that time and the secondary endpoints were as shown.

So these results were first as Dr. Kamat had pointed out, presented at SITC as a late-breaking abstract demonstrating complete response rates in the first seven patients up to nine months of evaluation. I'm happy to report that there's actually an additional three patients to the ones that are presented here who have been at least evaluated at the 3-month mark with two patients now have undergone their 12-month random bladder biopsies. And all of those patients have been complete responders to date.

The treatment adverse events were as expected, not very much different than those that have been shown in the Phase 1 and the 2 trials, mostly limited to the bladder toxicities Grade 1 and 2 in nature. No SAEs were reported, and there were a few lower grade immune-related adverse events. One patient had an autoimmune thyroiditis that was seen with the administration of pembro. There are some additional studies being done using CG0070, there's a Phase 3 monotherapy trial that's ongoing as well. And this is a registration trial enrolling up to 110 patients, also multi-center, multinational giving CG0070 and much the same way as we are in the CORE1 with the combination trial.

And so in conclusion, there are very limited treatment options for BCG-unresponsive non-muscle invasive bladder cancer. Adstiladrin or nadofaragene firadenovec had demonstrated a 53% complete response rate at three months and a 24% CR at 12 months. Early efficacy and safety data from the CORE1 study with combination CG0070 and pembrolizumab are very promising and additional studies of the adenovirus vector in both the non-muscle invasive and the muscle-invasive settings are ongoing and future investigations are planned. Thank you very much for your time.

Ashish Kamat: Thanks so much, Roger, for presenting the data on the gene therapy studies to date. Again you highlighted the key data from the key gene therapy trials. Obviously, our audience that's listening and viewing probably has heard about other gene therapies. And just in the interest of time, we can summarize to say that those aren't ready for discussion or presentation in prime time and that's probably why you didn't cover them.

So focusing on the ones that you did cover, especially the CORE1 and the BONDS since that's where you've been intimately involved with. And full disclosure, I've been advising you and other folks on them as well. Could you share with us what you think the true added benefit is of combining the two agents, pembro and CG0070?

Roger Li: Yeah. So that's a very interesting and excellent question. I think with the eclectic virus given its purported mechanism of action, it initially generates an immunogenic response in the bladder that brings in the killer T cell and other immune cells into the tumor microenvironment. So by itself, it's already doing something to the tumor from the immune standpoint. And then I think by adding on the pembro, you're augmenting that response by lifting the suppression of the T cells because of exhaustion.

So I really think that the two work in a very synergistic manner. We're trying to work out the specifics through some correlates that we're collecting from both the CORE1 trial, which I have described. And also another investigator initiative trial that I'm conducting here at Moffitt in the neoadjuvant setting, using muscle-invasive bladder cancer specimens that we're treating from the cis-ineligible group. But we're very excited to really work out the exact mechanism of synergism between the two agents.

Ashish Kamat: And then can you share with us a little bit about the BOND3 study. You went over the design but your thoughts on a single agent registration trial ongoing versus a combination, which really when you presented the data at SITC it was much better than I'm sure even you thought it would be, right? 100% CR that's maintained at least six months. And now you're saying some patients even at 12 months have a CR, which is really quite impressive. So yeah, share with our audience your thoughts on the pros and cons of having a monotherapy when you have such great results in combination therapy.

Roger Li: Yeah. So the monotherapy trial was really based on the preliminary studies from the monotherapy studies that have been done in the past. And again, I think we're seeing a lot of great efficacy with the combination trial. But I do think that there are some elements of added toxicity with giving the pembrolizumab in addition, especially going on for two years. Even though they're manageable as we've seen in the KEYNOTE-057 trial, but what sort of toxicity that we see from the combination of the treatments is still yet to be seen.

So I think from that standpoint, the monotherapy arm will be able to provide us with, first of all, a comparison study that we can unofficially compare the result, the efficacy results of between the monotherapy and the combination. But also another option of possibly reducing the toxicity, because as you know a lot of these patients in this setting are, they have a lot of other comorbidities making it impossible for them to even get the intravenous immune check on blockade therapy.

Ashish Kamat: So that's actually a perfect segue into the next question I was going to ask you with the pembrolizumab approval for BCG-unresponsive to CIS. We thought that we would see an uptick in the number of patients getting therapy and as you and many of the audience probably recognize it's not been adopted quite as well because of the potential systemic toxicity, the scheduling, et cetera. With nadofaragene results are very comparable to pembrolizumab, toxicity is lower, administration is much easier with one installation every three months. Now, of course, for various reasons that we can't get into, it's not yet been approved by the FDA.

But then that brings us to CG0070 where the toxicity appears to be very favorable. Obviously, you're still doing a combination study, but the installation schedule is a bit more intense obviously than nadofaragene for example. What are your thoughts in the way that will potential adoption of the agent in clinical practice? And are you doing any studies to see whether that administration schedule might be able to be ramped down after say an initial period off induction, so to speak?

Roger Li: Yeah, another excellent question. And that's actually a problem that we've been running into quite a bit as we're conducting these clinical trials. Because as you know a lot of patients will travel from far distances and the treatment schedule really is pretty rigid and it's pretty intensive. But nevertheless, I think the first step still is to look at the efficacy of what's been proven to work in the past in the earlier phase trials.

And we're actually in the planning phases of another study for intermediate-risk disease. So recurrent low-grade bladder cancer patients to treat with CG0O70 as well to prevent recurrence and to see whether we can use some alternative treatment regimens to combat that disease. So certainly I think the possibilities are out there. And the other thing is we have done some pharmacokinetics in the previous trials and we'll continue it to do pharmacokinetics.

The nice thing about using the oncolytic virus is that you can detect viral copies in the urine pretty easily to have an idea of how well it's being replicated within the tumor microenvironment. And based on those information, we can maybe draw some conclusions to how to best dose the treatments. So certainly that's a goal for ours, for patients' convenience, because that certainly is a very important factor to consider. But based on the information thus far, I don't think that we're quite there yet to reduce the dose.

Ashish Kamat: Excellent. Again, Roger, I want to thank you for taking the time and spending it with us going over gene therapy for bladder cancer. In closing, if you would take maybe 30 seconds to a minute and summarize the high-level data from CG0070 studies, that'd be great.

Roger Li: Thanks so much Ashish again, it's always been a pleasure talking with you about the different aspects of non-muscle invasive bladder and muscle-invasive bladder cancer and their treatments. So to summarize today's talk, I think nadofaragene firadenovec has been proven to be having very similar efficacy rates as pembrolizumab in the BCG-unresponsive CIS-containing setting.

CG0070 holds a lot of promise based on the preliminary data that we have generated both from the monotherapy arm and also especially in combination with pembrolizumab. That's been backed up by some mechanistic studies done in preclinical studies already. We're very excited about the results of the CORE1 trial as well as the BOND3 trial going forward and hopefully to bring this to the clinic for a lot of our patients in the future.

Ashish Kamat: Great. Once again, thank you so much for taking the time. Stay safe, stay well.

Roger Li: Thank you so much. You too.