Ashish Kamat: Arjun, welcome. It's always good to have you here to chat about things to do with bladder cancer. Arjun Balar is an expert in the field, Associate Professor at NYU Langone and a leader in bladder cancer. A lot of exciting things happening here at GU ASCO, right?

Arjun Balar: Mm-hmm.

Ashish Kamat: But the one thing that's on everyone's mind that people are not talking about that I want to ask you about is the approval of pembrolizumab, the first approval of its kind in the BCG-unresponsive space in over two decades. Tell me your view because you were closely involved with it in the actual approval numbers and the FDA process.

Arjun Balar: Yeah, so the study's history actually goes back many years, probably around the time of 2013, 2014 when initial conversations between the study sponsor would be Merck and the FDA. And it was such an interesting time because that was also the same time in 2013 that there was an FDA workshop along with the AUA where I think some very key individuals who are involved in bladder cancer research got together with the FDA and said, "Listen, there's just not been a lot of activity in bladder cancer, non-muscle invasive disease in many years. We need to get drug development going. And how do we do it?".

And it was at this workshop that a framework for this development process was kind of set in place. Some basic endpoints were defined, some efficacy thresholds that we would consider meaningful to the field and the duration of response which is particularly important in non-muscle invasive disease. In metastatic disease, we do tend to focus more on getting an initial response and then the durability is kind of the second component of it. In non-muscle invasive bladder cancer, those two are almost equal. It's not just the response, it's the duration of response. And so we had ideas of what landmark CR rates, which is what we were primarily looking at non-muscle invasive disease, what they needed to be at 18 months and 24 months and so forth. And it was around the same time that Merck was having these conversations and they developed a single-arm study mainly because randomization to cystectomy in high-risk BCG-unresponsive disease is just not feasible, and people have tried to randomize to cystectomy is not a feasible option.

So we decided the single-arm studies would be reasonable, and this study aimed to enroll two populations of patients. Both were BCG-unresponsive based on formal criteria that were also defined. And the cohort A, which was the primary focus of this study, looked at patients with carcinoma in situ with or without papillary tumors with CIS and patients were going into the treatment with the disease. And the primary efficacy endpoint was three months CR rate. And I'll touch a little bit on that for a moment, which is that why is it that we had such an early efficacy endpoint when many urologists will say, "Well, listen, after induction of BCG, if you give a little bit of course and maintenance, you can actually get a CR. And so why are we not looking a little bit further down the line?".

And the answer was that the FDA at that time was very conservative and they wanted patients who are not responding to quickly get off treatment and be counseled about cystectomy because we know it's highly, highly curative in this population. And so that's the evolution of this study. Ultimately, what happened was that 96 patients were ultimately what was what the FDA considered. The data showed that in those 96 patients who had met the formal criteria for BCG-unresponsive disease who were treated with pembrolizumab once every three weeks. The CR rate at three months was 40.2% or so, and that the durability looked at roughly a median duration of response of 16.2 months. Many would argue is that clinically meaningful or not. I think for most patients if that's a year and a half or close to a year and a half on average that I can keep my bladder if I have a response, I think most patients would say they'd take it. But what's really interesting is what that durability is really going to look like because we have some true longterm responders and we'll need to follow those patients out for two, three, four, five years. And there may be a subset of patients who can have durable remissions actually may be cured of their CIS without having needed a cystectomy.

Ashish Kamat: Right. It brings me to an interesting point, one that was raised at ODAC where we worked together and then afterwards in the urologic oncology community on the urology side.

Arjun Balar: Sure.

Ashish Kamat: So let me ask you this. What's your perspective on if you actually look at the 40% response rate and then take it out to the 12-month landmark benchmark that a lot of people mentally just translate in their mind? That works out to be about 19%, 20%. So when you have that number in your mind, how do you counsel your patient that's considering pembro in this particular space?

Arjun Balar: So, a very good point. We'll break down that data in kind of two components. One is the intent to treat, which is I think urologists and rightfully so are focused on, right? Which is of the patients who went into treatment, all 100 or 96 or whatever that number might be, what proportion of those are still in a response at 12 months? Or the way the data was presented, which is that since only the patients who achieved a response at three months could continue on to treatment, so no later responses, et cetera, could be observed only those patients. So then you're looking at a subset, right?

So to your point, I think the data that I think is most translatable to the urologic oncology community is an intent to treat analysis. So what that means and how I would counsel patients is that there's a one in five chance roughly that if you choose to receive this treatment, you will be in a CR at 12 months after you started treatment with the caveat that we can't get to 12 months without getting to three months first, which means you need a cystoscopy and cytology and document a complete response, and then you have a chance to be in that 20% later on down the road.

Ashish Kamat: Yeah, and that's an important point to bring up because a lot of people lose sight of the fact that you have an early signal readout at three months. And it's not like it's a year of wasted therapy or waste of time for these patients. Another question along those lines for you is obviously on the study design, patients were not allowed to be re-dosed if they did not have a CR at three months. But you've been treating patients with IO therapy for a very long time. You have a lot of experience in this. Completely off label, what's your sense about re-dosing patients? Do you have any that you've done that with? What would you advise our listeners?

Arjun Balar: So our enrollment and my participation in this study goes back to 2016 when we first enrolled our patients. And at that time a couple of my first patients on study, our urologists would have seen the patient's bladder before they started treatment, saw the patient's bladder at three months and said, "Look, I am seeing clinical benefit here. There's clear activity." But a biopsy is taken and it shows CIS and the patients came off study.

I had two such patients who did want to get additional therapy, and there are ways of accessing off-label pembrolizumab. We do actually counsel strongly against it primarily because it's a big unknown. And certainly, at that time, it was definitely an unknown of what the consequences of continued treatment might be both in terms of efficacy and safety. But a couple of patients did opt for that therapy with open eyes about their options. And for those two patients, we didn't see a subsequent response. However, in speaking to colleagues around the country and around the world who've also been part of this study, there are some patients who initially came off of study at three months who then subsequently had a CR based on their next cystoscopy, which was done as a standard of care.

The challenge is that we can't count those patients toward the primary endpoint. Those patients are off study and they are non-responders forever. However, it does follow what we do know about immunotherapy in terms of checkpoint blockade in advanced disease is that you can't always see a response when you first look, and in fact, we see delayed responses. We see this pseudo-progression that leads to a response later on down the road. And that's because unlike cytotoxic treatment, which works almost immediately in the sense of you instilled a treatment and you should see efficacy in a short period of time, immunotherapy engages the host immune system and sometimes it takes time for that immune response to evolve. And some of those patients are actually doing quite well even though they never achieved a response at three months.

Ashish Kamat: Right. The last point I want to raise with you today is we have a lot of community practice groups of urologists now looking at this and saying, "Well I want to start doing IO therapy in my clinic." And certainly not that they shouldn't be thinking about. But what would be your words of caution I guess when it comes to managing these patients and their AEs and just IO therapy in general.

Arjun Balar: So I share their enthusiasm. I think patients who are considering the choice of a cystectomy with BCG-unresponsive disease versus receiving treatment with pembrolizumab, I share the enthusiasm for anyone who wants to offer this to patients. The challenge is how to do it as safely as possible. You and I are privileged to be at academic centers where we have just an unbelievable amount of support system and specialists in various areas. But in the community setting, that may not be available.

And so my hope is that the urologists who wish to take this on, and ultimately I do believe that non-muscle invasive disease should be primarily taken care of by the urologists. They know the disease, they know the patients, they know the bladder and nothing can replace that. And so if they choose to take this on, then they have taken the educational steps they need to become as knowledgeable as they possibly can about the disease and also educate their advanced practice providers, their PAs, their NPs and RNs on the warning signs of immune-related toxicity, how to intervene quickly, and also have a list of specialists within various areas such as pulmonology, endocrinology, and gastroenterology, such that if an immune toxicity develops, that they're having a challenge monitoring and managing that other specialists can quickly intervene to make sure that these patients are treated safely.

Ashish Kamat: Thank you so much for taking the time out of their busy GU ASCO schedule. It's always a pleasure to have you. Enjoy the rest of your meeting.

Arjun Balar: Pleasure to sit with you.