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Petros Grivas: Hello, I'm Dr. Petros Grivas. I'm an Associate Professor at the University of Washington, Fred Hutchinson Cancer Research Center. I would like to welcome you all. We saw very exciting data in the field of urothelial cancer. And I'm very excited today, to host Dr. Karim Chamie, who is an Associate Professor in the Department of Urology at UCLA. He's also serving as the SU Fellowship Director for Urology at UCLA, and has made wonderful contributions in the field of urothelial cancer and GU malignancies, and had a very, very impactful oral presentation at ASCO 2022. Karim, welcome.

Karim Chamie: Thank you, Petros. Thank you for the invitation. Obviously, I'm honored to be here with you.

Petros Grivas: It's my honor. And I was so really thrilled to see your oral presentation at ASCO 2022. What a wonderful dataset. I know you led this trial, and for a long time, you have worked very hard on it. I would like to ask you to give us the background, the design and the key results, and take home messages on the QUILT trial that you led in the BCG unresponsive, high-risk NMIBC non-muscle invasive bladder cancer in patients, in the context, in the era we live in. Which assured us, testing the combination of intravesical BCG and the Interleukin-15 super agonist, the N-803.

Karim Chamie: Great, thank you. Patients with BCG unresponsive bladder cancer historically, have had very limited options. Right? So the patients were either offered Valstar, which was FDA approved 20 years ago, but found to be not very effective, and is hardly ever used, and very expensive, and really didn't change practice patterns, whatsoever. Or, a radical cystectomy. Those are the only two approved approaches for the management of patients with BCG unresponsive bladder cancer.

Obviously, over the last decade, we've seen significant advances, obviously, with the introduction of checkpoint inhibitors, and you've got the KEYNOTE-057 study, which demonstrated some efficacy in the management of patients with BCG unresponsive bladder cancer. The response rates were about 40%, complete response rates were 40%, and the durability was about a year. The other option was intravesical gemcitabine and docetaxel, which is not really FDA approved in this setting, but it's something that was conjured up over the last decade with folks like Dr. Mike O'Donnell at Iowa, and the group up in San Francisco, that put these combinations together, during an era where we had some shortages.

And what we found was that, some of those response rates were significant and were important, and we've been able to rescue some patients with BCG unresponsive bladder cancer. But really, from an FDA approved drug, we urologists, are looking for something that has significant durability. And so, we did initial clinical preclinical work with N-803 in mouse models. And really, by itself, it wasn't all that efficacious. BCG by itself, wasn't all that efficacious. But the combination of both really seemed to be quite effective.

And so, we did both a BCG naive and BCG unresponsive trial, and found that people who are BCG naive had 100% response rates with N-803 with N BCG. So we said, "Okay, if we see such a profound response of a combination of BCG plus N-803 in naive patients, maybe there's some efficacy there in unresponsive." So the FDA laid out some ground rules, as far as what BCG unresponsive drugs approvals should abide by. And they did allow a single arm study. The important point was, to achieve at least 30% complete response at any time. And the confidence interval, the lower confidence interval, can't be less than 20%. In order to get that number, you basically, have to get 80 patients. And so, that's why all BCG unresponsive trials are usually single arm. There are about 80 patients in that cohort. And these are patients that have to have CIS plus, or minus papillary disease. And ASCO and the FDA came up with this definition of BCG unresponsive, and we conducted this study.

And our study is essentially, vanilla, just like every other study that was out there in the BCG unresponsive, with the exception of one thing. And the only exception we had, that differed our study from all the others was, realistically, if you have a patient who has BCG unresponsive bladder cancer, and they refuse to get a cystectomy, if you see that they had high grade CIS, and then you give them N-803, and then they turn into high grade TA, do you really want to consider these patients failures? Do you really want to take their bladder out? And we said, "If we see some partial response, then we'd be willing to rechallenge those patients." And that's what we did in the study. And our study essentially is the same, with the exception of allowing patients to get rechallenged or reinduced. As long as they didn't have high grade T1, or worsening of their CIS, we allowed them to get rechallenged at the three month mark.

And what we found was, is that, if you give patients a full dose of BCG, and you combine it with N-803, you'll find that, at the three month mark, about 55% of patients responded, had a complete response. And if you rechallenge some of those patients that had a partial response, we get an additional 15, 16% of patients getting a complete response after a reinduction.

We presented this data at the AUA last year. And what we found is that, if you actually break out the patients who had a complete response at three months, versus those that have a complete response at any time, you'll see that those that had a complete response at three months have a much more durable response. And those patients who got reinduced at six months, their median duration of their response was only nine months. So it wasn't quite as durable.

But in our study, when you actually look at what we presented at ASCO meeting this year, we had a 71% complete response rate at any time. Again, 55% was at the three month, and then, 15, 16% was at any time. And the median duration of that complete response was about 26 months, which is pretty significant. And if you actually look at how these patients did, it was very well tolerated, from a safety profile. We think that A, maybe these patients are used to having lower urinary tract symptoms from BCG already. And we think, maybe the combination of BCG plus N-803, isn't quite as devastating as maybe some of these other drugs, like gemcitabine and docetaxel, on the bladder. And so, maybe the toxicity profile's a little better than some of these other agents.

As far as cystectomy avoidance, which is, I think, probably the most important endpoint here, the vast majority of the patients never went on to get a cystectomy. So if you follow these patients out, overall, the cystectomy rate was about 16%, and that includes those that responded and non-responders. So if you look at amongst those that responded, it was 9%, amongst those that didn't respond, it was 16%. And I think, that's the take home message, that only 16% of our patients ever went on to get a radical cystectomy. I think, that's the take home message here.

Petros Grivas: Thank you so much, Karim. Very insightful points, and you outlined nicely the difference in the design, between your trial with your group and the KEYNOTE-057, and also, in the context of the SWOG S1605 trial, with Peter Black and others. So you mentioned that, the clinical complete response rate at three months was 55%, which is still very high. And again, you cannot compare across trials, but definitely, looks higher than the checkpoint inhibition.

And you also mentioned the point that, maybe we have to rethink about an urgency to get these patients radical cystectomy, which has been the standard of care, in patients in unresponsive high-risk disease. What selection criteria would you use in your practice, as you learn from your trial, and the checkpoint inhibitor trials, and now the nadofaragene firadenovec trial, and the oportuzumab monatox trial. How would you select the patients, or think about trial designs that you feel more comfortable, or less anxious, for patients who may potentially forego cystectomy?

Karim Chamie: Obviously, this is a clinical trial led by urologists. And I think, when you have a urological led clinical trial, realize that urologists give BCG. And if a patient doesn't respond to BCG, we don't take their bladder out. We give them another round of BCG. In fact, if you look at some of the old studies that were actually done, some of the old SWOG studies, if you actually give BCG to patients, and you look at the three month mark, you'll look at their urine cytology, you'll still see urothelial carcinoma in a significant proportion of those patients, but you give them maintenance. You give them another dose of maintenance, and you'll notice by the six month mark, a lot of those cytologies go from being positive to being negative. And so, when you have that in your background, you realize that, there isn't that strong sense of urgency where you have to get this bladder out.

Michael O'Donnell actually looked at this historically, and found that, a patient can go on with having CIS that's BCG unresponsive, for probably about a year, before they actually are at higher risk of metastasizing. And then, when you have that as a context, as a background, then you don't necessarily need to jump the gun, and take their bladder out at the three month mark. And I think, that's the importance. I'm not saying you take their bladder out, two years, three years later. I'd say, you give them a three month trial, and if they don't respond, you give them another induction. And if they don't respond, then you can have that conversation. But from what you can see in our study, a lot of patients didn't go on to getting a radical cystectomy. A, because they responded. But partly because, there is this tendency that, this is non-muscle invasive bladder cancer, and as long as you adequately survey these patients, you're probably a little more comfortable following them.

Petros Grivas: Thank you, Karim. Wonderful discussion. And to your point, it's also, depending on the depth of the disease stage. Right? The clinical stage. Obviously, you are more worried, more urgent, for detecting for T1 disease or worsening CIS, for example, versus a more focal stable CIS. Although the staging is inadequate, for sure, in TA. Is that right? How much can you rely on that, and in the context of inadequate clinical staging?

Karim Chamie: So, yeah. I think, T1 is an important predictor. In our cohort A, 70% of patients were CIS alone, 20% were CIS plus TA, and 10% were CIS with T1. We also had a cohort B, of BCG unresponsive papillary disease. And again, in that cohort, 45% of the patients were T1. I think, if you actually look at responses, you see that the T1 patients didn't respond as well as the CIS, or the CIS TA. We did run a kind of force plot. And what you could see is that, if a patient had CIS with T1, the response rates were 67%. Whereas, if they were CIS alone, or CIS with TA, then it was a little higher. So 81%, if they're CIS with TA.

So I think, you're right. I think, if they have T1 disease, maybe you want to pull the trigger a little bit sooner. But again, a significant part of most BCG unresponsive bladder cancer patients are not CIS T1, a lot of them are just CIS.

Petros Grivas: Great discussion. The field is evolving so quickly, as you said, in the last 10 years we have seen a revolution in bladder cancer across the states, BCG unresponsive disease, neoadjuvant setting with a lot of Phase II, now Phase III trials ongoing, looking at checkpoint inhibitors, adjuvant setting, in a metastatic disease.

Let me ask you, Karim, we have intravesical chemotherapy as an option. You mentioned data with intravesical gemcitabine or docetaxel, or combination. We have intravenous pembrolizumab with safety approved, based on KEYNOTE-057 trial. The question for you is, do you foresee that the data you present, which look very impressive, I would argue, are enough for regulatory approval? Or you foresee the regulatory agency maintaining a randomized clinical trial in a disease setting, where the practically used standard of care may be valuable?

Karim Chamie: Yeah. I think the FDA made their bed, and basically stated that, you can get away with doing a single arm study in this disease space. And they approved pembrolizumab, even though they didn't really achieve any of the benchmarks that they initially sought out, back in 2012, 2013, at the AUA. And here, we have a drug that has blown it out of the water. And I think, it would be a little difficult to accrue into a trial, where you have a drug that has a complete response rate of, depends, whether you'd want to look at the three month only mark, and so, let's just say 55%, with a durability probably that hasn't been reached.

So if you actually look at the patients that had a response at three months, the median duration hasn't even been reached. And you have to randomize a patient to that, or pembrolizumab. I think, it'd be a little bit of a challenge. Especially, since this is not a very common disease. So these aren't patients that are just coming in left and right. This is still a relatively rare disease. And I think, that's the purpose of doing a single arm study. And so, I think, it'd be a challenge to accrue, and I think, it'd be a disservice for patients who actually have BCG unresponsive bladder cancer.

Petros Grivas: Got it. Got it. Great discussion. Obviously, visibility of a trial is important, whether you can accrue. We have examples of trials that could not accrue well in bladder cancer in the historical past, adjuvant chemotherapy trials, so on and so forth. So that's another consideration, whether you can physically accrue within a certain amount of time.

Maybe last question, Karim, before I let you go, extract your wisdom. In the context of a national BCG shortage, how do you foresee the combination that you presented going forward, hopefully, will have more visits in the future, but do you see that being a challenge?

Karim Chamie: So I think, everybody that's enrolled in the trial here has, we've been provided access with full dose BCG by the sponsor. I think, it's going to be something that, the sponsor will have to serve as a liaison, I think in the future, as far as getting access to the BCG. Now, if you ask me, and if you tell me, "Look, the sponsor can't supply you with the BCG, you're going to have to supply your own.", we're going to have to make ends meet.

Look, BCG patients, BCG unresponsive bladder cancer patients, there aren't that many out there. And what we've done at UCLA is, we've really been able to reduce the full dose BCG to those that absolutely need it. And so, for patients who have high grade TA, we've been giving them gemcitabine. Patients who have high grade T1 with CIS, we've been giving them BCG, sometimes full dose, sometimes reduced doses. But patients who have BCG unresponsive bladder cancer, really are the priority here. These are the patients that are facing a cystectomy down the line, if we don't have this last ditch effort. And so, what we've been doing at UCLA is, prioritizing BCG unresponsive to trials, as far as getting full dose BCG for those patients.

Petros Grivas: Great discussion Karim. Thank you so much for being thoughtful, being a great overall contributor in the field of GU oncology, a great mentor for your trainees and your fellows. Looking forward to learning more from you in the future. Thanks for presenting this data. Thanks for your time today.

Karim Chamie: Thank you, Petros. My pleasure.

Petros Grivas: And thanks to the audience for the attention. Stay safe, and stay positive in your mood, but stay negative, COVID 19 wise.