Alicia Morgans: Hi, my name's Alicia Morgans, and I'm an Associate Professor of Medicine at Northwestern University, where I'm a GU medical oncologist and I am thrilled to have here with me today a colleague and friend, Dr. Josh Meesk, who is an Assistant Professor of Urology, and biochemistry, and molecular genetics, and we work together in the Polsky Urologic Cancer Institute at Northwestern University. So, thank you so much for being here with me today, Josh.

Joshua Meeks: Thank you so much for having me, Alicia. I always love to come and talk about bladder cancer and what our updates are.

Alicia Morgans: Wonderful. So, speaking of updates, you just returned days ago from the SUO meeting 2019. And I think that every SUO, we are faced with new advances, particularly as it comes to bladder cancer. So, can you share some of the highlights from this year's meeting for us?

Joshua Meeks: Yeah, this was a great meeting, Alicia. So, the SUO 2019 in Washington, D.C. And I think this was probably the biggest changes that we saw, the biggest results that came out, were really in the setting of BCG unresponsive bladder cancer. We were all so sort of very eagerly awaiting the results of the Phase III trial from Nadofaragene firadenovec (Adstiladrin®) that was carried out by the SUO-CTC. And so, just to kind of to walk back, the Nadofaragene firadenovec (Adstiladrin®) is a viral therapy that's given in the bladder that expresses interferon and this is an exciting thing that sort of started with one of our members.

So it started in Colin Denny's laboratory, and then translational work that resulted in a clinical trial. And the SUO Clinical Trials Consortium, the SUO-CTC, is really where this has gone, and it's gone really fast, to do a Phase II, Phase III multi-institutional trial as quickly as they've carried it off is an impressive result for this group. And that's one of the reasons we were really happy to kind of see these results.

If you remember the Phase II was published in, sort of at the end of 2018, and it was actually very impressive, 30% CR for CIS at three months and then overall a 50% recurrence-free survival at 12 months. And so the thought was that really if these results held up in a Phase III fashion, that this would be our first agent that potentially could be approved by the FDA for BCG Unresponsive Bladder Cancer since valrubicin. And valrubicin is the only thing that's FDA approved. And overall, just so you know that the 12-month response rate is anywhere from 10 to 15%, and even though it's approved, no one uses it. It's just not a great drug that in the therapy is just not put into practice in clinics across the U.S. So, despite the fact that there's one drug, no one uses it.

And really, this has been an enormous open space in bladder cancer that no one's had a great therapy for. And, because of that, the FDA has actually approved people to do Phase III single-arm trials. And that's what this... Yeah so, this trial was a Phase III single-arm trial. It was a total of about 157 patients enrolled, 107 with CIS and 50 with papillary disease.

There was a pathologic review. So, those numbers went down to a total of 151, roughly two to one carcinoma in situ to papillary cancer. And the way thatI Nadofaragene firadenovec (Adstiladrin®) is given is actually pretty impressive in that it's given in the bladder, and it's good for three months. So the patients get treated on day one and then they get a dose at four months, seven months and 10 months. And that's it for a year.

So, if you think about all we do with all of our other therapies where they're just bringing patients in, chronically giving them a drug, the real benefit of this potentially if effective, is the long time between doses where it's pretty well tolerated. At least the Phase II data looked like it was well tolerated and you can go a long time, but that could be really a patient-friendly way to treat it. And I also... I hate to break it down by provider lines, but as urologists, we were all very excited about this because it seemed like for the longest time everything was kind of moving away from the urology clinic and being infusion-based for this world.

So this is a therapy that urologists could give, which there's a lot of urologists who have really kind of wanted this to work. So, everyone was excited to see these results.

Alicia Morgans: So, it's impressive I think in that, just as you're saying, this isn't giving treatment every week. It is not comfortable for patients in many ways to get these intravesical therapies, though certainly better than maybe an IV chemotherapy. It is still fraught with challenges. So being able to give something less often still intravesical, the urologist is still in control, still has that ownership with the patient. And that's great.

And what I think is actually even more impressive and important is that this is probably as it continues to move into practice, going to be able to help save peoples' bladders, which is also very patient-centric goal if this is a BCG unresponsive population, and if you can prevent a recurrence, that's hugely important to patients. The other thing that I think is so interesting about this data is that it looks like it's particularly effective in papillary disease. And I'd love to hear your thoughts on that.

Joshua Meeks: Well, I think the hard thing to separate that out is, is it truly working well in papillary disease or is that disease more surgically resectable? I think the data's still out on that. I think the overall papillary disease tends to be more "treatable", more resectable than carcinoma in situ. I think about carcinoma in situ as a field of fact. I think it's a harder nut to crack.

You can't surgically resect... It's unlikely you can resect most of CIS as opposed to papillary disease, which for the most part, it's sometimes it's kind of like whack-a-mole, where you're removing these papillary tumors, but at least you can see what to resect. Now, in the age of Cysview®, you may be able to see a little more CIS, but I don't think most people approach carcinoma in situ in a surgically resectable manner.

Alicia Morgans: And that makes total sense. So, it's important for us, I think as clinicians interpreting this data, to understand that difference that CIS can be more insidious, can have a broader range. We can use tools to see it more effectively. Papillary may be more responsive to our TURBTs and perhaps that's why we see such a high rate. But either way, this drug looks like it is making a difference for patients. So where do you see this in terms of moving forward from SUO? Where is this Nadofaragene firadenovec (Adstiladrin®) going to go?

Joshua Meeks: So just to look at their data that they presented in SUO. So, this cohort was interesting. So, they had a group that mostly was treated at least three prior lines of therapy, which is normal for them. Once again, two to one CIS. The CR rate at three months was around 58% which when you look at that it's 73% papillary, 54% carcinoma in situ. But if you look at the 12-month data, so this is ultimately what their primary objective was. It was 24% response for CIS, and then 44% for papillary disease. Now you realize that what's interesting about that is they required an end of study biopsy, which is kind of not always required. So, before what we would manage our people as cytology and they would look at the bladder to see what they would see, but they actually put in their end of study biopsy, which changed the outcome for six patients in the trial.

So, they were visually negative cytology, but a biopsy was positive. So, that may, if looking at protocol design, that may be something that the FDA may be requiring in the future, but a 24% response for CIS, I think that's better than what we've got. I think that's a key outcome to keep an eye on as far as the bar, that the extra thing that the secondary objective was durability.

So if you responded, how long would that continue? And the overall durability was just as good. So the durability for CIS was about 45% and for papillary disease about 60%. So, I think there are going to be two things that we look at going forward is, A, do you respond? And B, how long will you respond? And as far as trying to think about what's going to be approved and what's used, I think they're both going to be indications that we'll be looking at in the future.

So for example, we know from the early Keynote-057 data that the response rate is about the same, maybe a little bit less, but the durability as we know for checkpoint therapy is very good. So, that may be the strength. But I think those are both windows that we'll be looking at in the future.

The last thing I'll say about Nadofaragene firadenovec (Adstiladrin®) is that the tolerability is incredibly high in that there are very few patients who had a problem. I mean the biggest problem was frequency, the second was fatigue. But there are very few patients that ended up coming off the trial, and the grade threes were like three to 4%. The big thing we worry about with these patients is progression, they had a 3% progression rate to muscle-invasive bladder cancer.

Now, the interesting thing about them is three of the four were T1. So, I think the good news is that this is a space that we will continue to use these different therapies and going forward. And there's a bunch of patients that we'll continue to... We can treat, but I think the only concern we have to keep an eye on in the future is these T1s, because they seem to be a very high-risk population and perhaps they may be someone that we need to put in a special risk category.

Alicia Morgans: Absolutely. So, the final word on the Nadofaragene firadenovec (Adstiladrin®) SUO-CTC Phase III study for patients and for clinicians who are listening?

Joshua Meeks: I think this is the beginning of the next era. We're going to have therapies available. I think we're going to have good drugs to treat patients. The big question is which drug is going to work with each patient? And I think the biomarker data is really going to help us in the future.

Alicia Morgans: Absolutely. So we look forward to that. So thank you so much for sharing this today, Josh. And I look forward to talking to you again in the near future.

Joshua Meeks: Thanks, Alicia.