Sam Chang: Hi. My name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center, and we are quite fortunate to have one of our graduates from Vanderbilt, Dr. Kelly Stratton, who's associate professor urology at Oklahoma. He completed his fellowship Memorial Sloan Kettering, and really has done some innovative research, not only in bladder cancer, but in kidney, as well as prostate cancer, looking at disparities as well, but today he is going to focus on intravesical instillation options and those that are exciting to him, pros and cons, et cetera, so I'm going to turn it over to Dr. Stratton, and thanks very much, Kelly, for spending some time with us.

Kelly Stratton: Thank you. It's a pleasure to be able to talk about this very important subject for patients with bladder cancer. So, here's our outline. In high-risk BCG-unresponsive, non-muscle invasive bladder cancer, there's still unmet needs. There's several current approved treatments, and we'll mention those, but there's also some emerging treatment options with immunotherapy, combined with BCG, and we'll get into that in N-803 or Anktiva. We'll also talk about some ongoing trials and immunotherapy combinations that are exciting and should report out in the future. I'll mention my own personal experience, looking at a Avelumab + BCG in a phase 1b study that we did here at the University of Oklahoma, and some future directions for patients with high-risk, non-muscle invasive bladder cancer.

The unmet need? Well, there's a lot of patients who are unfit or unwilling to undergo radical cystectomy, who failed BCG, they want to maintain their bladder, and they're looking for additional treatments. We know that when we treat patients who are BCG-unresponsive, that there's a high rate of recurrence, so it's really important for these patients that we get something that will control them, prevent them from having recurrences, and ultimately preserve their bladder. Our goal is to not only control recurrence, but potentially improve quality of life. I think that's really important, and there's some emerging data that our thought that taking out a bladder would have a large detrimental impact on quality of life. Maybe we have to revisit that. There are also limited biomarkers to select patients who may be responsive to these subsequent treatments.

When we look at the landscape of approved treatments, there are several new therapies out there that, I think, are really exciting, and we're hopeful that this will change the way that we treat BCG-unresponsive in NMIBC. The first is N-803 or Anktiva. It has a long, generic name. This is a treatment that is combined with BCG in patients who are BCG-unresponsive. The next is Adstiladrin. It is a nadofaragene, a non-replicating adenovirus that we use for patients who have BCG-unresponsive, non-muscle invasive bladder cancer. Then, we get into the infusional immunotherapies; pembrolizumab, which has been approved, and additional treatments that are kind of on the horizon are being investigated. Gemcitabine/Docetaxel is combined chemotherapy in TAR-200.

When we look at N-803, it's a combination with BCG, interleukin-15 super antagonist. It activates NK and CD8 T cells, and this was evaluated in the QUILT 3.03 trial, looking at BCG-unresponsive CIS with or without Ta or T1 disease. The results were very impressive. Complete response rate 71% at 3 months, and really, what you can be most excited about is the durability of response. So, the median durability response was 53 months with a cystectomy-free rate at 3 years of 84%, and when you look at it long-term, the disease-free survival, 99%. So, this study using N-803, trade name Anktiva, showed that combining immunotherapy with BCG was really exciting and effective. There are also several other ongoing trials, looking at combining immunotherapy with BCG. KEYNOTE-676 is looking at BCG+ Pembrolizumab. There's also the CREST study, the POTOMAC study, the ALBAN study.

Then, there are some studies that have combined different agents as well, like the ALLIANCE study, you're at intravesical Gemcitabine with pembrolizumab and an NRG study looking at pembrolizumab plus radiation versus chemoradiation for patients with BCG-unresponsive in NMIBC. In my own personal experience, I use the combination of Avelumab plus BCG in a phase one study. Avelumab is very unique, in that it has a potential for antibody-directed cell mediated toxicity for the cancer cells. So, we were looking at combining this with BCG to see if we could get a synergistic effect. There are some animal studies that showed that Avelumab was more reliant on a CD4 T-cell response, and so we thought that BCG may stimulate that response or help augment that response and accentuate that Avelumab.

Additionally, Avelumab had been tested in a novel, weekly regimen in patients with lung cancer, and so we wanted to take advantage of this weekly administration cycle to couple and synergize it with BCG. We looked at this in about 18 patients, of which 83% were able to complete their induction, and that was reaching our primary goal. Looking at response rate, at three months, we had 73% who had a complete response rate at 3 months and 67% at 6 months, so we felt like that was indicative of a positive signal in these patients, and we're excited and encouraged to see what the results of these upcoming immunotherapy trials are and potentially expand the use of Avelumab as well. So, future directions?

Well, we're really undergoing a paradigm shift, where we're trying to preserve more bladders in patients using a series of intravesical and immune therapy related treatments. We think that, as these treatments improve, that sequencing and timing may lead to more patients being able to preserve their bladder. We know that combined treatments have really improved our responses. Anktiva would be one of them, and there are others as well that maybe are on the horizon. We can look forward to checkpoint in addition to BCG, and those results should be forthcoming. Then, our hope is that biomarkers will help us identify patients who may benefit the most, in that we can treat patients strategically based off of what we think would be most likely to yield a response.

Sam Chang: Kelly, that was a great overview of current options that are available, exciting trials that are yet to be reported in meetings. Some are, some are in the works, and then even earlier trials as things are being developed, so just wanted to touch base on a couple of things. We've had cystectomy kind of as the standard therapy that is the recommended treatment as these patients have continued disease despite BCG. So, one question to ask for you is, we know about Dr. Gore's CISTO trial, looking at patient reported outcomes. Tell me what you think about, in today's world, cystectomy as a treatment option for patients with non-muscle invasive disease? Should it still be the recommended treatment? Should it now be an option? Kind of tell me your thoughts regarding that.

Kelly Stratton: Well, I do think it should still be an option, and that recommendation, I think, really will boil down to patient education, their preferences, and their tolerance for risk. Some of the exciting data that got out of, for instance, the QUILT study, is that patients, that durability of response, that disease-free survival, there was a long tail on that. And so, the worry, and we saw this with prostate cancer and active surveillance, is that we may miss a window of opportunity, and we're not picking up that signal, as far as are we putting patients in a worse spot by giving them these intravesical therapies? So, I think that there's a window of opportunity to create some sequencing to create some time for bladder preservation to see what the natural history of their disease is, to potentially introduce biomarkers, and to know that we can still salvage patients later down the road with cystectomy if necessary.

Sam Chang: So I think you bring up a really important point, is this kind of struggle between, "Oh, we've got these options. Let's try these options," so that's one part of the struggle, is how we sequence. Then, you add the fact of, "Okay. When do we pull the proverbial trigger of, let's move on to cystectomy? Are we just delaying the inevitable? Are we adding cost toxicity in terms of social of responsibilities, not only the patient, but to the family, et cetera?" So, talk to me a little bit about how you see sequencing and how we should best study that, and are we just spending too much money, too much effort, et cetera for these intravesical therapies?

Kelly Stratton: Well, certainly, costs can be a factor, but it's not one that we can control very well, and so it's hard to really alter that, but if you look at the response rates that we're getting in some of the more contemporary trials, say a 30% response rate, that means that we save 70% of patients and about 30% move on. We've seen that be a marker of success in other cancers, where we can pull out a group of patients who may need to move on to surgery, but we can preserve other patients and continue following them going forward. So, I think if we can identify patients who have more aggressive disease, those who may not respond to treatments, that we'll be able to incorporate these strategically into a way that builds a long-term strategy towards bladder preservation. So I do think that the patients benefit from it. They certainly want it. There's a strong desire from our patients to maintain their bladders, and they're asking us, come up with a treatment plan that allows me to keep my bladder that does so safely and with a tolerable treatment.

Sam Chang: Yeah, no. I think your points regarding that patient driving it, it clearly is the majority of patients, and you understand that. When you look at the fact that the disease specific survival rates remain high in all these studies, as we try different agents, that there is a risk, unquestionably, but it is small and giving patients the opportunity to try an intravesical therapy or combination intravesical systemic or intravesical chemotherapy, et cetera. Makes sense. The last question, Kelly, and this is a tough one, but you have such experience on different forms of immunotherapeutic intervention in different diseases. As you see intravesical options, because I think urologic surgeons really prefer that, tell me your thoughts of chemotherapy as a whole, immunotherapy as a whole, antibody-drug conjugates as a whole. Tell me your thoughts regarding how you think a combination of this will play out.

Kelly Stratton: That's a tough question. It certainly is. So we have multiple different interests involved in bladder preservation, from combined chemotherapy, like Gemcitabine/Docetaxel, a whole body of work that's being looked at and scrutinized. Then, the systemic immunotherapies, which we're seeing, just like in other cancers, moving up earlier and earlier in the disease site, and we're starting to see responses that are significant earlier and earlier, more meaningful. Sandwich therapies around the time of surgery. Then, also intravesical therapy. So, I do think that there may not be a right answer to your question, but the urologist is the person who's going to answer any questions that we can answer, and so it's our job to own non-muscle invasive bladder cancer and to tease out the right sequence and order and structure for what will be most helpful in bladder preservation for BCG-unresponsive patients. I don't have the answer. If I did, I would write a nice article that would outline that, and it would be fantastic, but...

Sam Chang: No. Really good point. I had to end with that one, because you're right, right now it's not answerable, but I do think it's the responsibility of clinicians and surgeons to develop trials to help try to determine the answer to this or at least accumulate the data of, "Okay. We've tried this. We've moved to this. How did people do?" So, I think, realistically, in today's world, the registry data is going to be very, very important as we get more and more information about these different interventions, how we use them, how we sequence them, and ultimately how patients feel about them. So, I really applaud all the efforts that you've made for a long, long time, looking at different forms of immunotherapy in bladder cancer, and look forward to perhaps kind of the next follow-up trials with your Avelumab. As always, it's really good to spend some time with you, Kelly, look forward to seeing you in the near future.

Kelly Stratton: Yes, thank you.