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Zachary Klaassen: Hi, my name is Zachary Klaassen, Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined on UroToday by Dr. Trinity Bivalacqua, who is a urologic oncologist at Penn University.

Today we're going to be discussing his EAU presentation, looking at updated clinical and translational results from the BOND-003 Cohort C. Trinity, thanks so much for joining us and discussing your research with us.

Trinity Bivalacqua: Thanks, Zach. I'm happy to share with you and the audience some updated results, both clinical results as well as some of the translational results from the phase III trial, which looked at cretostimogene in patients with high-risk BCG-unresponsive non-muscle invasive bladder cancer with CIS.

So these are my disclosures. As it relates to the background around cretostimogene, I think it's now established that this is a form of oncolytic immunotherapy with a dual mechanism of action, which includes viral replication, resulting in tumor lysis as well as stimulation of the immune system. This is-- this occurs via a highly immunogenic adenovirus, which, under the regulation of the human E2F-1 promoter, selectively works to-- work on tumors that are RB pathway alterations or deficient.

It also encodes-- and this is a very important point. It codes for GM-CSF transgene, which is actually the portion of this oncolytic immunotherapy that relates to immunogenic and upregulation of the immune system.

Now, by way of background-- and I think important to update everybody as to this. This was a phase III trial. It did enroll 112 patients. So this, by definition, is the largest BCG-unresponsive trial with 112 patients to look at a therapeutic agent to treat CIS plus or minus papillary disease.

So cretostimogene was administered in patients with, either CIS plus or minus papillary disease, who meet the strict criteria for BCG unresponsive. They undergo an induction course with an evaluation. If that evaluation shows evidence of high-grade disease, they are allowed to get a second induction course. This is very similar to one other trial in this disease space.

The primary endpoint is CR at any time. So complete response at any time. But importantly, we-- additional endpoints include a CR at 12 months duration of disease, as well as cystectomy free survival and progression free survival.

Now important, this trial, unlike some of the others in the disease space, do require a mandatory biopsy at 12 months, which allows us to better define the efficacy of this oncolytic immunotherapy in this disease space.

Here are the patient demographics. Predominantly male, white, greater than 65 years of age. Importantly, these are heavily pretreated population of patients. The median amount of BCG instillations was 12. And this is predominantly a trial that looked at CIS only. Patients with CIS alone, with 80% representing the disease space.

It was actually about 25% women, which is actually high for clinical trials.

Now, here's the updated data. This is now different than the previous presentations at the SUO. The overall complete response was 75.5%. This is at any time. And importantly, the 12-month CR rate was 46%. It's an excellent response rate at 46%. And at 24 months, there were 30 confirmed CRs but have not reached the 24-month time point beyond. Ninety-seven percent were free from progression to muscle invasive disease at 12 months, 90% cystectomy free survival at 12 months, and all complete responses were centrally confirmed and CR was consistent across all disease types.

Now, when we look at the duration of response at 12 months, the estimated duration of response at 12 months is 63% with a median DOR, which exceeds 28 months, and the median follow up is 22 months. Once again, different data compared to that which was presented at the SUO, which was only 14 months. So we now have an extended median follow up of 22 months.

And as you can see here, the duration of our probability of response at 24 months is actually 58%, which holds true to the 12-month percentage.

We look at the safety profile. No grade 3 toxicity, consistent with other cretostimogene trials and importantly, the grade 1 or 2 toxicities, the median time for these treatment-related adverse events was only one day, and there were no treatment-related discontinuations. And 97% completed all protocol defined treatments. So only one day where patients had symptoms.

Now, when we-- we now take the clinical findings and try to look at how this relates to the translational findings. This was where we looked at GM-CSF in the urine, as well as the cretostimogene titer in the urine. And you can see here in the round circles are pretreatment of creto. And then in the triangle is post administration of creto.

You can see that the GM-CSF, which is in a red or dark red, you see a rapid increase in GM-CSF after the first and second treatments, which then stabilizes at treatments 3 through 6. And we can see here, once again, the increase in the creto titer at all doses, demonstrating that you have a sustained local delivery for about four to five days after an effective payload delivery.

Now, when we look at the maintenance phase, this mimics what we've seen in the induction phase, where you see an increase in both GM-CSF as well as the creto titer.

Now, when we looked at these two additional findings, we evaluated preexisting adenovirus antibodies and also looked at the cretostimogene titer. And you can see that the adenoviral antibodies increase with each dose of cretostimogene. And this was actually looked at in the serum. So these adenoviral antibodies which looked at the serum, whereas the cretostimogene was in the urine. And we see that there's a stable antibody and anti-tumor response over time. And this actually correlates with responders.

So what we're looking at here is actually patients that have response clinically. Also, we see this stable adenoviral antibody response.

Now, this is an important piece of data because it showed that there was no systemic spillover of creto. And this-- so, therefore, there was nothing seen in the systemic or serum as it relates to creto levels. It remains below the level of detection.

So key takeaway points here is that this is a highly effective, very well tolerated regimen, translational data validates sustained local activity dose treatment schedule and actually correlates-- the responders correlate with clinical efficacy. And importantly, there's no post creto close contact precautions that are necessary considering there is no systemic spillover of creto seen in this phase III clinical trial.

Thank you very much, Zach.

Zachary Klaassen: Trinity, fantastic data, great presentation. We've now seen a couple updates on this data, and it continues to have excellent efficacy and safety. As we see continued updates, we're going to see final results at AUA.

How does this sort of place creto in the non-muscle invasive disease space? Where does this lead us?

Trinity Bivalacqua: Yeah. I think what the data shows, at least what was presented in Madrid. And I suspect that the data presented at the AUA will continue to show a very nice clinical response and durability if it is FDA approved. We're still waiting for registration and for approval. I suspect that it will position it very well as probably the go to for BCG unresponsive space for a couple of reasons.

One is because it's safe. It has good efficacy and more importantly, it actually is given intravesically, in a dose in a way that all of our urologic clinics are accustomed to. It's given intravesically. It's given via the BCG SWOG maintenance protocol. And I think that allows urologists to be very comfortable with this.

And I think the most recent data, which shows that there is no systemic spillover and that there's local-- that there's no major local symptoms, will allow a lot of pharmacists and a lot of clinical practices to be very comfortable with this disease, with this treatment modality.

Zachary Klaassen: Yeah, absolutely. And I think you showed some very elegant translational work. And I think congratulations to the trial and CG Oncology for doing that.

Where does that go from here? And is it possible this could help with patient selection in any way?

Trinity Bivalacqua: Yeah, I mean, so what-- Zach, I've got to give credit to Colin Dinney who also had a presentation at the EAU, which I'm not sharing you that data, but I'll tell you what that data shows, which is that we're actually able to measure minimal residual disease, genomic disease in the urine.

So we're able to see those patients that have minimal residual disease or no disease are responders, and they're not showing any recurrence, whereas those with urine tests that show minimal residual disease, looking at genomic testing, we're able to say, hey, these are patients that are going to recur.

So I suspect that in the future, what you're going to see is a combination of biomarkers, as I've just shown, as well as what Colin presented and his team presented at the EAU, which will allow us to be able to escalate care in those patients that need it and hopefully be able to de-escalate care and those that don't.

So I actually think this is exciting. And I mean, I look forward to running additional clinical trials which are demonstrating this, demonstrating how we can combine creto with potentially something else to be able to capture those patients that are non-responders.

Zachary Klaassen: Yeah, great answer. I think-- very exciting. We're excited to see the final results in a little bit as well at the AUA. Always great chatting with you, Trinity. Any take-home messages, anything we didn't hit on that you want to bring up with our listeners?

Trinity Bivalacqua: Yeah, I mean I think the BCG unresponsive space is very busy these days, right? We've got a lot of really-- we've got some FDA-approved medications that are also being utilized. We've got other things, other therapeutics that are hopefully going to be FDA approved in the future.

So I think this disease space is actually just exploding, which is exciting for a lot of us in the field, as you know. But it also can be confusing, right? So what are we going to use?

I think ultimately the therapeutic agent that's going to be used the most is the one that's efficacious, safe, and easy administrative route. So that's how I see the field.

Zachary Klaassen: Yeah. Great summary. Trinity, thanks so much for joining us on UroToday to discuss the BOND-003 Cohort-C update.

Trinity Bivalacqua: Thanks, man.