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Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic oncology at MD Anderson Cancer Center.

It's a distinct pleasure to welcome once again to our forum Dr. Colin Dinney, who really needs no introduction, but I'll just say that he's an expert in bladder cancer. He's Professor and Chair of Urology at MD Anderson Cancer Center. He's one of my personal mentors and he truly is a mentor to all of us in the field, especially with his leadership and his development of a gene therapy all the way from the lab, from the days when I was actually a trainee with him, to now where it's available and should be available for patients to use in the clinic.It's a pleasure to have one once again on our forum to be able to share his expertise with us and our wide viewership. Thank you in advance to UroToday for giving us this opportunity.

Colin, with that, the stage is yours.

Colin Dinney: Thank you, Ashish. Again, thank you for inviting me to present the development of Adstiladrin Gene Therapy for BCG Unresponsive Disease.

Here are my disclosures that are relevant to this presentation today.

Now, as we know, we have a clinical dilemma. BCG's our most effective therapy for treating non-muscle invasive disease but over time, most patients will eventually recur. It's been reported that up to 35% may die of bladder cancer. So, alternative therapy is indicated, but until recently, only valrubicin had been FDA-approved for BCG refractory CIS with a complete response rate of only about 18%. So it was clear that effective second line therapy was an unmet need for patients facing cystectomy.

With this in mind, in 2012, the SUO, the AUA, and the FDA launched a collaborative effort to address this deficiency and to define a pathway for drug registration for what is now known as BCG unresponsive non-muscle invasive bladder cancer.

As you know, the trial designs evolved over time from 2012-2018 when the FDA released their guidance regarding trial design. The FDA will accept a single-arm trial with a mixed population of patients provided that they meet the stringent definition of BCG unresponsive disease. But the FDA has made it clear that the primary endpoint will be a complete response rate for patients with CIS and the approval will be for CIS. But once an agent is approved, patients with high grade Ta/T1 disease could be treated off-label or perhaps the label could be extended to include them.

As you can imagine, there's a lot of agents under development. We're familiar with various chemotherapy agents such as gemcitabine and docetaxel. But we know this has been really been tested mainly in the BCG exposed population, which, it's a related population, but not quite as strangely defined as BCG unresponsive. A lot of trials looking at BCG plus something else, other immunotherapies, toxins, and gene therapy.

These are the agents that have completed registration trials. I mean, Vicinium completed the trial, but some issues came up at the FDA review so that the development of this drug has been put on hold. Pembrolizumab was approved in 2019. ALT 803 and BCG is coming up for approval. We know we're talking today about nadofaragene.

So why did we pursue interferon alfa gene therapy for non-muscle invasive disease? Well, we long recognize that interferon has a pleiotropic antitumor activity, it can be directly tumoricidal through TRAIL-induced cytotoxicity. It's anti-proliferative and it's anti-angiogenic. Today, there's a lot of interest in its immune activity. It's involved in antigen recognition and processing. Also, NK and T-cell activation.

We know from clinical experience that intravesical interferon protein was largely ineffective due to limited tissue exposure to interferon after bladder instillation. So recombinant ad-interferon with Syn3 was developed to overcome this limitation and to provide high, sustained levels of interferon in the urine and bladder tissue. Syn3 is the excipient that allows for gene transfer across the urothelium.

Why did we use an antivirus type 5? Well, it's a reliable vector, it provides good transduction efficiency, it has broad tropism for numbers for various cancer cells and normal urothelium, there's little risk for integration in the host genome, it has sufficient trans-gene capacity to deliver a large payload, and it's modestly immunogenic, which may be a good thing. Recently, they've developed the mechanism for large scale production, which is necessary for commercialization.

Early on, we did a phase one trial of adding Ad-interferon Syn3 sponsored by Shering. It was a standard dose escalating phase 1 trial. In this trial, we did not encounter any dose-limiting toxicity, were able to demonstrate effective gene therapy by measuring interferon levels in the urine and after treatment, and while it was a phase 1 trial, the clinical results were promising and that supported a phase 2 trial.

Now the phase 2 trial was actually run by Society of Neurological Oncology Clinical Trials Consortium. The results were published in JCO in 2017. In fact, this manuscript was selected as one of the top JCO articles for GU malignancies in 2017, in which we reported a 30% complete response rate for CIS and a 50% high grade recurrence-free survival for high grade Ta/T1 disease at 12 months. Again, the drug was well-tolerated with manageable adverse events.

The promising data supported the phase 3 registration trial, which was recently published in Lancet Oncology. Again, the trial was run by the Society of Neurological Oncology's Clinical Trials Consortium.

The primary endpoint was a 53% complete response rate for CIS at three months. All of our CRs were at three months because we did not allow for re-treatment at three months for patients with persistent disease because we're one of the earlier trials, we were concerned about a disease progression. In fact, this is the only time you can really directly compare our results to that achieved with ALT 803 and BCB because the differences in trial design. At three months they reported with combination therapy a complete response rate of 55%, which is comparable to what we achieved with monotherapy with Adstiladrin.

About half the patients with CIS maintained their high grade recurrence-free status to 12 months. For patients with high grade Ta and T1 disease, 73% were high grade recurrence-free at three months and 60% maintained that status at 12 months. That's important because late recurrences beyond 12 months were rare. In distinction to a lot of the other trials in our space, we had a mandated end of study biopsy, which identified occult disease in 10% of those individuals who would've been considered to have been free of disease on clinical grounds, with this biopsy. Eight patients, or 5% of the patients on the trial progressed, but six at the eight, or 75%, had a history of T1 high grade. Knowing what we know about the high risk of understaging in this stage, it's likely that some of these patients had muscle invasive disease at the time they entered the trial.

We also found acceptable safety and tolerability. Only one grade 4 adverse event related to drug or procedure, and that was sepsis secondary to the catheterizations. No patients died from drug or procedure-related adverse events. There were only three treatment-related serious adverse events and only three patients, or 2%, stopped treatment due to a treatment-related adverse event. No pattern of immune-related adverse events. We long recognize the convenient dosing schedule; one intravesical therapy every three months. We concluded that it still did provide a favorable benefit risk profile for patients facing cystectomy.

I mean, I'm just showing you a comparison between Adstiladrin and pembrolizumab, which has been approved for the same disease state. There were some differences in the trial design. For instance, Adstiladrin trial was 100% of the patients were US. The pembro study was an international study; only 35% of the patients were American. The three-month complete response rate for CIS was 53% in Adstiladrin, 41% with Keytruda, but only 31% in the US population. The 12-month complete response rate for CIS for Adstiladrin was 24% with a biopsy. If we had not performed the biopsy, it would've been 27%. Pembrolizumab was 19% without.

If you look at the 12-month complete response rate in the US population, while all of the patients on Adstiladrin trial were Americans, it was 24%, you have to estimate it for Keytruda because they didn't present that data. But if you look at the CR rate in the US population and the variability, it would be estimated at about 13%. If you look at treatment related grade 3 and 4 adverse events, it was 5% for Adstiladrin, 13% for Keytruda. Serious adverse events were only 2% with Adstiladrin and 8% with Keytruda.
One of the other benefits for Adstiladrin, at least for urologists, is that urologists can deliver this in their office. Whereas in many institutions, you need to get medical oncologists to actually deliver pembro.

Again, just now when you're looking at these single-arm trials, there are considerations for comparing them. For instance, the time point for defining a CR following the first dose of a study drug will determine the response rate. We've seen, for instance, that the complete response rate for ALT 803 and BCG is improved over 20% by using a six-month endpoint that allowed for re-treatment of persistent disease at three months, and re-treatment was not allowed either in the pembro study or in the Adstiladrin trial.

When comparing trials that employ combination therapy, and it's offered with BCG versus those with monotherapy, you need to consider the contribution of the second drug to the response rate. Because even in patients with BCG unresponsive disease, at least 20% will achieve a CR secondary to BCG, and that's probably a low estimate. I think you need to, in a single-arm study, consider an end of study biopsy as it does identify occult disease and does minimize investigator bias.

Finally, I just want to conclude, the efficacy and safety of Adstiladrin has been confirmed by a phase 3 trial, and we're pleased with the results to date, but we do feel we can improve upon it. One way to do that is to improve patient selection by identifying patient characteristics or biomarkers that predict sensitivity or resistance. This will improve the response rate by selecting likely responders for treatment. The focus is on the development of urine and serum biomarkers because as we know, tissue for patients with CIS is scarce, and if we have a urine biomarker, you can do this evaluation in real time without the need for biopsy. We're also evaluating alternative vectors that might improve transfection efficiency, and then developing novel combination strategies, targeting resistance mechanisms.

Before stepping down, I just want to acknowledge all the individuals who worked on this project over the last 20 years, the majority from MD Anderson and now from Johns Hopkins. Early on, Bill Benedict, Dave McConkey, our host, Ashish, and Bodgan Czerniak and Neema Navai. But the majority of these individuals are all people who rotated through our laboratories as fellows during their time at MD Anderson. I want to also recognize our colleagues from Finland and of course the SUO CTC site PIs, staff, and their patients who supported the phase 3 study, 33 sites, and our colleagues from Canji and Schering who were the pioneers for the early work of developing gene therapy. Thank you.

Ashish Kamat: Thanks, Colin, for that very succinct presentation. You packed a lot of information into the presentation. Let me ask you a couple questions to try and help our audience a little bit.

You compared Adstiladrin with pembrolizumab and showed the difference in response rates. One of the things that you didn't touch upon was the ease of administration and the convenience for the patient.

Can you comment a little bit based on your experience, just with all the drugs that you've studied over the years, how would this be something that you think would be beneficial for patients, many of us who have to travel a long distance? Yeah.

Colin Dinney: Yeah. So I think if you look at all the drugs that are being developed to date in this space, I think Adstiladrin would be the preferred drug by patients and physicians alike.

Number one, we have the convenient dosing schedule; only one treatment every three months. That was especially helpful during COVID when we wanted to minimize patient visits to the hospital.

Also, the tolerability is good, the efficacy is good.

Also, now that they've changed the manufacturing, so now when it becomes commercial, it'll be available as a ready to use formula so that, actually, you don't even need the use of a pharmacy to give it. You can put it in a -20 degree freezer and freeze it. So that means that physicians in practice, not just at cancer centers or medical schools, can have access to the drug and just give it in their office, without the need for a pharmacy. I think that's a tremendous benefit to everybody.

Ashish Kamat: Yeah, that's a big improvement because you hear the fear that people have about viruses and reconstituting that in their clinics or in the community and having a closed system for the drug would be really beneficial. Is that a done deal or is that being developed?

Colin Dinney: No, no, that's the formulation that was developed. That's why the manufacturing took a little longer to get it approved by the FDA.

Ashish Kamat: Okay, great.

Colin Dinney: That's accepted and it's a done deal.

Ashish Kamat: Excellent. Again, talking about viruses, especially since you've just come out through the pandemic with coronavirus, could you talk to our audience and explain to them why this viral therapy is safe, that people shouldn't be afraid of it like we are with other therapies?

Colin Dinney: Yeah, that's a very good question. So this virus has been altered. The E1 gene that regulates replication has been removed. So the drug is a non-replicating adenovirus, so the virus is present transiently. Also, the virus is not incorporated into the host genome. So you don't have the risk for insertional mutagenesis. AIDS was a virus, it was incorporated into the genome. That risk has been largely been eliminated.

Also, this virus is very similar to the common cold virus and the concern is that maybe that if you've had a cold recently, you may not respond to drugs, you might have antibodies. Well, strangely enough, the response to the agent is actually higher in individuals who have antibodies to adenoviruses in their systemic antiviral antibody titers.

So I think, you can tell your patients that you're not going to get sick for this virus. It doesn't replicate it. We don't find it in the serum after delivery. So it's very safe.

Ashish Kamat: Right. With the approval of pembrolizumab and of course now Adstiladrin, and congratulations on that, and we expect other drugs to hopefully be approved, as well, what is your advice to people out there on the optimal sequencing of therapy for patients after they have recurrences, after BCG? Is there some sort of a cheat sheet that you would recommend they follow?

Colin Dinney: Well, I have greater knowledge with the viral products that are being used. I think that one of the consequences of viral gene therapy with interferon is potentially the upregulation of PD-L1, and that could be a resistance mechanisms for those patients that don't respond. So I think that a potential sequence would be to treat patients with Adstiladrin, and then if they recur, then you could consider combining their treatment with an IO at that point in time, as opposed to going straight to cystectomy. The research has uncovered that combination. There's other combinations that would potentially be useful, but they have to be further evaluated. But I think that's an obvious potential combination. I mean, Adstiladrin is probably the better tolerated and so I would use that first and then if patients didn't recur, I'd go with the combination study.

Ashish Kamat: Again, speaking of recurrences, obviously on the study we weren't allowed to re-dose patients that had a recurrence, but over the years we have learned just following these patients closely that a recurrence at three months, unless it's T1, is not really as much of a death sentence as we used to believe. So do you think in the real world you would recommend or advise people to consider re-dosing?

Colin Dinney: Yeah, I mean, looking back, if there's one thing I could have done differently designing the trial would've been to allow for re-treatment at three months. But again, we have to remember, we're one of the first trials out there and we were concerned about the risk for progression and we felt that was a risk, and so we didn't allow for it. But again, it's been proven to be safe and I think that, again, if I had to do it over, I would allow for retreatment at three months, with the exception of patients who progressed to T1 or had persisted T1.

Ashish Kamat: Correct. Colin, you said, again, you were one of the only studies, and of course the single-arm paradigm and you brought out the nuances of the single-arm paradigm. Do you think moving forward the consensus of the community and maybe the FDA, and I don't know if you could speak to what they were thinking, but the community in general is that we are done with single-arm studies now that we have approved agents? Or you think there's still a role for single-arm studies?

Colin Dinney: I mean, I think there's still a role for single-agent trials, at least with the current studies are ongoing. I mean, I think in the future, that we're going to be seeing more combination trials with agents that are approved. Again, to move forward with saying with an Adstiladrin plus another agent like an IO, I think you'd have to do a randomized trial. I mean, the natural randomization, in my mind, would be IO plus Ad versus Adstiladrin alone. Then what I would do is I would follow the patients and then at three months, if the patient on Adstiladrin had a recurrence, I'd randomize them again. It'd be a large study, I'd randomize them again to a second dose of Adstiladrin versus Adstiladrin plus IO, to answer two questions, whether a second dose of the drug at three months was efficacious, and whether delayed combination therapy was as effective as upfront combination therapy.

I mean, those are the kind of trials I would see coming. They'd be large trials, but I think they would answer really, really important questions in how we can use these drugs most effectively in our practices.

Ashish Kamat: Clearly, the work that you alluded to, which you're doing, of course with the biomarker and patient selection, all of that's going to be very important.

Colin Dinney: I mean-

Ashish Kamat: Colin, you and I can talk on this forever. I mean, we do often talk on this forever.

But in the interest of time, if you want to leave our audience with a few closing thoughts or high level points to take home?

Colin Dinney: Yeah, I mean, what I would say is I think that there's a lot of room for development of drugs for non-muscle invasive bladder cancer. I think working closely with the FDA has been the secret to making a lot of progress in the last couple of years, and I think that's really critical. I think as we develop more drugs, that we're going to have to spend some time trying to figure out which drugs are effective for which patients. Then we're going to have to rely on developing biomarkers and potentially looking at patient characteristics to help us do that. I think it's going to be clear that as we move forward, we're going to be able to identify the appropriate drug for the appropriate patient. We all talk about that, but it's actually very, very difficult, as you know. But I think that's where the focus should be once we have these drugs, putting together novel combinations based on resistance mechanisms and trying to figure out who's going to respond to what.

Ashish Kamat: Right. Once again, Dr. Dinney, thank you for taking the time from your busy schedule and spending with us, and thank you UroToday.

Colin Dinney: Thank you. Take care.