Bladder cancer is the sixth most common cancer in the United States and ninth most common worldwide. While the FDA approved the Bacillus Calmette-Guérin (BCG) cancer vaccine in 1990 for the treatment of superficial, non-invasive bladder cancer, oncologists today are excited about a new class of immunotherapies called immune checkpoint inhibitors. New immunotherapies have significantly reduced the risk of recurrence for bladder cancer while also increasing the percentage of patients who see a complete response post-surgery. Dr. Arjun V. Balar, director of the Genitourinary Medical Oncology Program at NYU Langone’s Perlmutter Cancer Center, discusses the potential to further improve outcomes for patients with this disease and answers questions from the audience. We will discuss how oncologists predict patient response to immunotherapies, common mutations in bladder cancer, length of treatment, and other topics. Don’t forget to submit your questions to Dr. Balar.
Tamron Hall: Welcome back. We are joined by Dr. Arjun Balar, who is the director of the Genitourinary Medical Oncology Program at NYU Langone Perlmutter Cancer Center and is an assistant professor in the Department of Medicine at the NYU School of Medicine. Dr. Balar, Brian, thank you for being with us today.
Dr. Arjun Balar: Thank you so much. So, we’re going to be talking about advancements in bladder cancer with regard to immunotherapy and the timeline in advanced bladder cancer. Well, I mean, really begins in the 1970s when we first started using intra vesicle BCG. It demonstrated activity and non-muscle invasive bladder cancer, and many of my urologic oncology colleagues will tell me, “Listen, guys, you know, we were the first ones to develop immunotherapy and bladder cancer,” and they are right for saying that, and it demonstrated significant activity based mostly on generating a localized immune response.
Then for the next 30 years, we really didn’t see much activity, at least, you know, with regard to new immune therapies. We use platinum-based chemotherapy, especially for people with, you know, muscle invasive and metastatic or advanced bladder cancer. Sobering data it extended survival. It was beneficial to patients, but it was not a cure, at least not for the majority. There was probably a subset of patients for whom it was a potentially curative treatment, but for the vast majority, it was not.
Then in 2016 and moving forward, you know, we had we had breakthroughs really, you know, leveraging some of the major advancements beginning in the early 2010s with checkpoint antibodies with, you know, the phase one trials first being tested in all solid cancers, but many of the first insights and developments in advanced melanoma, and then slowly but surely, we started testing these checkpoint antibodies in other cancers, bladder cancer was eventually going to be tested, and frankly, we found some really promising trial data in 2014 with the first phase one trial for Atezolizumab and then 2016 the first accelerated approval for Atezolizumab in 2016. It was the first FDA approval in 30 years. It was an incredible advancement, and then 2017, it was the first positive phase three trial, and over 15 years it showed a survival benefit for pembrolizumab. Shortly thereafter, nivolumab, avelumab and durvalumab were approved, and these were all checkpoint inhibitors that targeted the same PD-1 pathway. So, PD one or PD-L1 antibody, and then in 2017 into 2018, both pembrolizumab and atezolizumab were approved as first line treatments in metastatic urothelial cancer. So, in 2017 was when they were approved and 2018 the labels for those drugs were modified. Now those were modified primarily because we had a better understanding how best to use those medications in the first line setting because as we know, metastatic, you know, metastatic urothelial cancer, you know, to this date, we still use platinum chemotherapy and in selected patients we use, you know, platinum chemotherapy still preferred as the first line treatment, but in other patients, immunotherapy can still make sense, but the culmination of all of these trials told us that immunotherapy is effective and can lead to durable responses in patients between 20 to 30% of the time. Now we’re seeing evidence from clinical trials showing that it’s even active in patients who are undergoing cystectomy or bladder removal for their bladder cancer, then just a few weeks ago, we had the first approval for immunotherapy for patients who’ve had bladder cancer, a cystectomy for bladder cancer and who may be at risk for relapse, at high risk for relapse, and we have a trial that demonstrated a disease free survival benefit, which essentially shows that it reduces the risk of relapse when we give immunotherapy in the after setting, essentially saying that we can maybe prevent these relapses in metastatic disease entirely.
So, what is it that we’re looking at in the future, right? In 2019, we saw evidence from clinical trials looking at immunotherapy in combination with a new class of drugs, the new kids on the block called antibody drug conjugates. One such candidate of that class is a medication called Hne four to Mab vedotin. These new medications essentially take an antibody, which is like a homing molecule that is specific for protein that is uniquely expressed on the surface of cancer cells and then delivers a very potent cancer molecule directly to the cancer and then limits the exposure of normal healthy cells to that anticancer fighting drug. Then we have found that when we combine immunotherapies with certain antibody drug conjugates that maybe we can really, really ramp up the percentage of patients who benefit from treatment upwards of 70 to 75%. Those are really, really high numbers. Then not only can we get those cancers to shrink, but perhaps we can get them to shrink for a long time. Early evidence from a phase one trial suggests that those responses can last potentially for years. Now those are really enticing data. We need to test them in larger trials, and those trials are happening now, so we’re really excited about those trials in 2020 and beyond, we’re using immunotherapy now in localized muscle invasive bladder cancer. You know, there is some sobering data as well. When we combine chemotherapy with immunotherapy, we found that it wasn’t as beneficial as we had hoped, much like what we see in lung cancer, we don’t see as much benefit as we see. We don’t see that benefit in lung cancer. We don’t see as much of that benefit in bladder cancer. However, if we use immunotherapy shortly after chemotherapy, that seems to be quite beneficial. So really, what we’re understanding is that we’re, you know, immunotherapy clearly is extremely important in the treatment of bladder cancer, but over the years, what we’re teasing out over the last couple of years is exactly what the right sequence is and what right combination, et cetera, what are the right partners? That’s really the charge of all of us in the academic field is to figure out what is the right way to use immunotherapy to maximize the clinical benefit for all the patients who are suffering with this disease. There are many more trials that are currently underway ipilimumab, which you know many of us in the immunotherapy field are familiar with. It’s a CTLA-4 antibody, the very first checkpoint antibody approved combination with nivolumab. I think that’s going to have a very clear role in advanced urothelial cancer, urothelial bladder cancer. Higher doses of this medication seem to make a difference, whereas in other cancer types, it may not be so. I think in urothelial bladder cancer appears to be the case. There are more modern versions of interleukin two, which is one of the oldest immunotherapies that we use first relevant in kidney cancer and also in melanoma, but pegylated versions which allow us to give it in a kind of a more tolerable form in the outpatient setting. I mentioned again, antibody drug conjugates the new kids on the block, which I think are not just relevant in bladder cancer, but also other cancer types. Then the one other class of medications I haven’t really talked much about are FGFR inhibitors. These aren’t immunotherapy medications. These fall into the class of so-called targeted therapies, but these are also really relevant in bladder cancer, and we’re finding some evidence now that you can also combine these medications with immunotherapy for clinical benefits. So, a lot of advancements in the last five or six years, making up for 30 years before where we didn’t see much in the way of clinical development. So, a lot of hope for the future and a lot more work that needs to be done.
So where are we today? Right. So, immunotherapy is a major component for the treatment of metastatic bladder cancer. That’s undoubtedly the case. Whether it’s the first line or the second line or is in maintenance, it is firmly established in metastatic bladder cancer. It is also firmly established in localized bladder cancer, whether it’s non-muscle invasive in for patients who, let’s say, have BCG, unresponsive bladder cancer and who don’t want a cystectomy or are not candidates for cystectomy or also in the after or adjuvant setting after cystectomy for muscle invasive bladder cancer, and then, as I mentioned, there’s clearly novel agents and combinations under investigation in each one of these disease states that I just mentioned. So, a lot more work that is underway and in the future. So that I’ll close and open up to questions.
Brian Brewer: Well, thank you so much for that introduction around immunotherapy for bladder cancer. One thing that really stood out to me was the emphasis on combination treatments. I think when people hear about immunotherapy, they may think that’s the new thing, and I don’t have to get another form of treatment, but you actually brought up a few examples where combinations happen. Let’s talk about that. Like, how do those combinations, why do they work better than one thing alone?
Dr. Arjun Balar: Yeah, that’s a great question. I think that’s something that we’re still trying to tease out, right? So, and we figure it out through clinical trials. So, the first thing that you address is combinations, right? So, it comes down to which combinations, you know, the most relevant ones, I think to our patients today is number one – does immunotherapy combine with chemotherapy and does it combine with chemotherapy well to my benefit. So, if I’m a patient, does that make sense for me. Right now, the evidence from two very, very important clinical trials tell us that it combines safely. There’s probably an improvement in response and which means the percentage of patients where there’s major shrinkage in the cancer, but it’s not sufficient enough that it’s like bang for buck this is what I need to be doing, and for reasons that we don’t fully understand, and there may be a subset of people, people who where we combine the medications, where they may be some antagonistic effects between the chemotherapy and immunotherapy that we just don’t understand yet in bladder cancer that may be different than in lung cancer. However, when we combine immunotherapy with antibody drug conjugate specifically in format vedotin so far, the evidence that we’re seeing, the reason we might be seeing such an increase in that response rate, you know, that number that was in that 70% range again, albeit small study forty-five patients. What we hope that the reason is that these antibody drug conjugates, or even maybe what we hope for with chemotherapy is that it induces a phenomenon called immunogenic cell death, where the cancer medicines that one of those drugs, the chemotherapy or the antibody drug conjugate, is killing the cancer cells in such a manner that it enhances the immune response and so that the immune therapy can come in and work even better. That’s the that’s the rationale and by kind of the synergistic interaction that the immunotherapy then works better, and then that leads to the immune system kind of carrying the way eventually in the end and then leads to a remission. That’s the idea. But we have to prove it in clinical trials.
Brian Brewer: So, for a patient who is considering his or her treatment options is combination, something they should focus on or what’s the best approach when facing a diagnosis at whatever stage you have?
Dr. Arjun Balar: Yeah, so it depends on the stage, right, so the stage is absolutely critical for patients with metastatic disease, number one, see an expert in the field. If they have access to clinical trials that address, let’s say, a combination, then I think that that makes sense. Outside of a clinical trial, I think that the standard of care is either platinum-based chemotherapy alone or potentially immunotherapy alone if the patients can’t, you know, if an individual is not able to handle, let’s say, platinum chemotherapy or simply is, you know, not wanting platinum chemotherapy, then immunotherapy could potentially make sense. However, based on the current evidence today, really platinum chemotherapy, which is either cis platinum or carbon platinum, remains the majority of patients that that is really the standard of care. However, it seems that and the reason is because we can really get cancer under control with chemotherapy more often than we can with any and then immunotherapy. However, right now, when we use immunotherapy immediately after chemotherapy is when we seem to get the best benefit from immunotherapy. That’s the current evidence today outside of a clinical trial in localized cancer. That’s where we use immunotherapy as well.
Brian Brewer: I would love to hear more about that. So, you’re seeing that the time when you’re giving a patient immunotherapy after or before another type of treatment matters, and that’s what we’re all looking at to see. What’s the most effective thing?
Dr. Arjun Balar: Then the last part was, you know, in the stage of disease. So, in localized bladder cancer, this is where I think, you know, we’ve just had a lot of advancements recently and we’re still sorting it out. In muscle invasive bladder cancer, we just had a recent approval, and so for patients who’ve had, let’s say, neoadjuvant chemotherapy and a cystectomy, which is removal of the bladder, they may still be at risk for systemic relapse, which means recurrence of the bladder cancer in other parts of the body. Here we have definitive evidence from a randomized trial showing that the addition of immunotherapy afterwards reduces the risk of that relapse over time, and so there’s a clear benefit for use of immunotherapy afterwards. However, there are still more trials that are going on that may say, well, even immunotherapy before the surgery might make sense. Perhaps immunotherapy in combination with the antibody drug conjugates before and after surgery might make sense. So, while we have certain approvals that have happened now, there’s so many trials that are happening, and so the data that I might tell you about today, you know, at the next CRI conference next year, in 2022, I might tell you something completely different.
Brian Brewer: The science is moving very, very quickly on this, so that point is very well heard, you talk about recurrence and administration of immunotherapy to prevent or lower the risk of potential recurrence. I would really like to hear more about that. What is effective and what is not?
Dr. Arjun Balar: So, the systemic immunotherapy is given in the after setting, and so that that’s trial was Checkmate 274. Right, and that study looked at the treatment specifically was adjuvant nivolumab and looked at a group of patients who received neoadjuvant chemotherapy before cystectomy for muscle invasive bladder cancer. The story in this specific clinical scenario is that if that cystectomy specimen, which is the cancer specimen that’s removed, still has cancer in it, that is invasive. The likelihood of systemic relapse, which is development of cancer and other parts of the body, like the lymph nodes, the lung and the liver and the bones and other scary parts can be as high as 60%, 70% or more, depending on how much actual cancer is in the bladder and the lymph nodes. So, and up until recently, you know, we would have that, you know, information from the pathology specimen inform patients and say, “Listen, this is what we have.” but there wasn’t anything we could do about it, frankly. However, now with this information from this trial, what we now have is definitive evidence showing that if we do, the standard of care right now should be neoadjuvant chemotherapy surgery to remove the bladder, and if there is persistent muscle invasive cancer, the addition of immunotherapy reduces the risk of systemic relapse by essentially, you know, 20 to 30%. That’s where the hazard ratios demonstrated over time is that we can actually reduce that risk.
Brian Brewer: Can you briefly explain to our viewers the difference between neoadjuvant or adjuvant setting? What does that mean?
Dr. Arjun Balar: Yeah. So, you know, the medical world is full of a lot of jargon, right, so we use adjuvant to mean “after” and neoadjuvant to mean “before”. Why is it that we don’t just say before? I don’t know, you tell me. So, we use neoadjuvant to say before definitive local treatment for a cancer. So, let’s say for breast cancer, it would be breast surgery, if it’s colon cancer, it’s colon removal, and for bladder cancer, let’s say it’s, you know, bladder removal, and so it’s neoadjuvant would be any treatment that’s given before that bladder removal and then adjuvant treatment is any treatment that’s given afterwards.
Brian Brewer: Thanks for that clarification, we have a question coming in from one of our viewers about how does this person know or how do the doctors know that he or she may be more responsive to immunotherapy than other patients with bladder cancer?
Dr. Arjun Balar: Yeah, that’s a phenomenal question, I think that’s a question that unfortunately, we still don’t have a really great answer for, and I’ll tell you that it’s not for a lack of trying. So what we have done over the years is try to measure different proteins in the tumor specimen, in particular PD-L1, and that’s a protein that we can measure more readily using different antibody stains, so we can sample a tumor specimen, you know, measure the amount of that protein that’s present and, you know, to some varying degrees, studies have shown that the more of that protein that is present in the tumor specimen, the more likely that that cancer specimen and the patient who has that cancer is going to respond to that immunotherapy. What we have found is that through, you know, subsequent, you know, more rigorous testing that protein level and the subsequent correlation to response to immunotherapy has been inconsistent. I think the reason we’re finding that out is because the immune system is extremely dynamic and we can’t really measure it in a static environment. So, we’ve tried other gene expression signatures and other things as well, but it seems to be less consistent. There are other clinical factors as well. So short answer is that we don’t have yet a reliable measure, and so we use a lot of clinical judgment. We use a lot of randomized trials. We also compare it to what other standards may be out there, and many times it’s a gestalt in clinical judgment that that drives a lot of our decision making right now.
Brian Brewer: I’ve heard again and again in the course of this summit series from CRI, but also just in speaking with patients who’ve been treated with immunotherapy or other types of treatment for cancer that it really does come down to the individual and in a way like every case is unique and different. Are you seeing at least broad strokes? You mentioned this PD-L1 as a potential biomarker, but are there other things that give you a sense when treating a patient that this may or may not work? Or how do you even approach that?
Dr. Arjun Balar: Yeah. So, it boils down, so I will tell you that that is a decision that I will try to summarize by simply saying that that’s the decision I often make kind of in the room. It’s between myself, the patient. It’s a gestalt of the patient, the blood work, what the cat scans show. You know, our personal preferences about treatment where they are in their lives, right, where they are in the course of their treatment, what other options and treatments they may have even somewhat mundane things in the grand scheme of things like how far are they traveling from, you know, a home to their treatments? You know, what social support systems might be in place or do we live alone? Is there you know what access to care might there be if they develop side effects from a variety of different treatments that we’re considering? So, a lot goes into it. But you know, when we boil it down, if I were to try to try to simplify it as best as I can in metastatic disease, where I think that’s where some of our treatment decisions are really challenging, it really boils down to first line or second line and beyond. In the first line setting, we have clear choices. It’s either platinum chemotherapy or immunotherapy, and so far, the evidence tells us that outside of certain situations, really, we should be using platinum chemotherapy because that seems to benefit most patients. However, there are certain scenarios where I might use immunotherapy, where the safety of platinum chemotherapy might be a real challenge for the individual, or the clinical scenario might present itself that immunotherapy really has a good chance of working. The cancer is limited in its scope. It’s limited to the lymph nodes. It’s not presents in extensive form, it’s not progressing quickly, and there are not a lot of symptoms related to the cancer itself in those scenarios. Immunotherapy is more likely to work if the cancer is progressing very quickly. Really, we have to use chemotherapy, a blunt tool. In second line and beyond Immunotherapy has been shown to be beneficial as better than single agent chemotherapy in most patients, and that’s where immunotherapy has to be something that we come comes toward the top of us of our list of choices.
Brian Brewer: So, what I’m hearing is every, again, every patient is unique and has his or her own circumstances. It sounds like a very complicated decision, right, that that someone should discuss with their oncologist and their health care team. How? Just curious. I mean, how? How do those conversations go? You know, when someone is learning about a diagnosis for the first time and let’s say the disease has progressed. How do you how do you embark on that conversation?
Dr. Arjun Balar: Yeah, I mean, I think that I think with experience and time, you know, my conversations have changed a bit, right? There was a time, you know, eight, you know, five, six years ago, maybe a bit longer where they were more directed and more limited in scope because we didn’t have a lot of tools available to us. We had chemotherapy and then more chemotherapy, and unfortunately, you know, when you have not a lot of tools available to you, sometimes the conversations are brief and yet more sobering than you ever wanted them to be. But now they are much more hopeful, and it’s because we have a lot of tools available to us and we have a lot of trials and our trials are now really, you know, while I’ve talked about standard of care, whether it’s platinum and immunotherapy and at centers like where I work and other academic centers, where we have access to studies where we’re really pushing the edges of immunotherapy and combinations, et cetera where we are, I steer most of my patients toward clinical trials, which are really using immunotherapy as the as kind of the backbone, and we’re combining other agents on top of it. We’re seeing much more, much more promising outcomes. We’re seeing responses, deep responses that are lasting for potentially years. They’re much, much more hopeful where I can say, you know, with confidence that I don’t know what the median survival could or could not be that I don’t know what years one, two or three could be because we are seeing such potentially long-term excellent outcomes in our patients, many of whom that I started on trials in 2016 or 2015. You know that I that I see now every, you know, three to four months or every six months, and so, the conversations are longer because the complexity of the decisions are more and I have so many options available that, OK, well, let’s see what is the right choice for you because we have so many available choices, right? So, I think that it’s they’re much brighter discussions, much more hopeful discussions now than they ever were before.
Brian Brewer: That’s wonderful to hear, and you know, survivorship is an amazing word to use when talking about getting through a cancer diagnosis or continuing to live through a cancer diagnosis and continuing to respond to treatment, and so it’s really, really wonderful and encouraging to hear that you’re having these longer conversations with more people. I think that’s a sign of progress. Absolutely. So, I do have another question that are coming in, these questions are coming in live right now. “What about side effects?” So, we really haven’t spent a lot of time talking about that and I know that side effects can be common from immunotherapy to immunotherapy, not even based on cancer type, but I’d love to hear any specific concerns for bladder cancer patients.
Dr. Arjun Balar: Yeah, that’s a great question, and I know that obviously is as part of your, you know, conversations that you’ve had today, you’ve probably covered a variety of different, you know, immunotherapy side effects broadly, but there are, you know, some side effects that I have observed clinically that are a bit unique to patients who have bladder cancer and they’re, you know, somewhat expected. I guess if you’re someone like me who treats bladder cancer every day and there have to do with the urinary system, right? And so just kind of a little bit of a crash course for, you know, for, you know, for the non-neurologic oncologists is that, you know, the urinary system is colonized with bacteria. You know, there’s this misconception that the urine is sterile. It’s actually not. There is a urine urinary microbiome. There are normal bacteria that should be present within the urinary system, usually in very low quantities. So, under normal conditions, we are not able to culture urine for those you know, bacteria. That’s why when if you get a urine culture, it doesn’t grow anything. But if you were to throw a lot of culture and media into there, you could actually grow it. Why am I describing this? That’s because when patients develop bladder cancer, the microbiota change and they actually become much more, much more pathogenic type of bacteria. What I’ve seen is that when we start immunotherapy in some patients, I’ve seen more UTIs and a quote-unquote sense, and I think the reason I see more of those in patients starting immunotherapy, I believe, and this is my thought, is that because the presence of the immunotherapy activates the immune system and perhaps to some degree within the bladder and kind of agitates the bladder, there’s local inflammation and the symptoms of activating those bacteria and the interaction between the bladder mucosa basically simulates the symptoms of a UTI, and though some patients need antibiotics, sometimes within one or two weeks of having started immunotherapy, so I’ve seen that a bit more often. The other thing that I’ve seen is that patients who develop bladder cancer often smokers right they’re most often smokers. It’s the most common, one of the more common smoking related malignancies, and so watching out for immune related pneumonitis, not that there is necessarily a higher risk for immune related pneumonitis, but the ability to handle it and to be able to physiologically handle some of the consequences of it. You have to monitor our patients much more closely because the cardiopulmonary reserve that’s what I describe is the ability to withstand the effects of it. You know, we’re much more careful about monitoring our patients on immunotherapy because of that risk of pneumonitis.
Brian Brewer: So, you’re saying pneumonitis sounds like an inflammation of the lungs that’s a potential autoimmune response or autoimmune related response. So that is something that doctors and patients will want to be aware of if that’s happening. Is that correct?
Dr. Arjun Balar: Exactly. It doesn’t happen often, at least with single agent immunotherapy, where we’re just using one of the immunotherapy drugs like a PD-1 antibody like nivolumab or pembrolizumab, you know, significant events three, maybe four percent of the time. However, it’s something that patients have to be aware of, that these things can happen, and if you already have, let’s say, COPD or emphysema and then you develop this on top of that, that can be a real challenge, right? So, you know, the moment you develop any changes in the symptoms of your breathing, your breathing pattern, that’s an immediate phone call. Because you know what I tell my patients that if you have trouble breathing on a Monday, but I don’t find out about it until Friday, I’ve given your immune system a five-day head start to, you know, to cause inflammation in the lungs, which is again, pneumonitis, and we have to treat that aggressively with steroids.
Brian Brewer: I think that’s very good advice, I think, for any patient receiving immunotherapy we hear that over and over again, the littlest symptom, just share it. Report it, you never know. It could be potentially fatal like that is a serious condition. The UTIs I had not heard of, so I’m interested in hearing a little bit more about that. Do you know why we get these more dangerous bacteria?
Dr. Arjun Balar: Yes. So, I think, you know, once the bladder tumor develops, it exposes the underlying tissues below the urothelium. It disrupts the entire anatomy of the of the of the bladder mucosa, and so like biofilms, develop biofilms or, you know, basically, you know, normal mucosa that, not normal mucosa but abnormal mucosa, where bacteria would like to basically attach and adhere to once those bacteria attach and colonize. They are basically impossible to get rid of, and so these are, you know, classic gram negative. These are a type of bacteria that commonly cause urinary tract infections. Basically, you know, stick on, you know, to the sides of bladder tumors and are very difficult to eradicate. This is, by the way, many times why patients who initially develop or have symptoms eventually get diagnosed with bladder cancer initially have symptoms of recurrent urinary tract infections. Get antibiotics. Those symptoms resolve, and then they keep coming back, and then eventually they find out that the underlying reason behind all of this was a bladder cancer. So, this is a very common scenario for patients who are ultimately diagnosed with bladder cancer. Now, that’s not to say that everybody who has recurrent urinary tract infections has bladder cancer. That’s the that’s the rarity, right? But that’s the that’s an often a common presentation underlying story.
Brian Brewer: Is this something that you discuss with your patients before putting them on immunotherapy like this is a risk or how prepared patients for side effects?
Dr. Arjun Balar: Well, everyone in our clinic and certainly our nurse practitioners, you know, do as well. Say, listen, when you’re first starting the first day, if within the week you have symptoms of urgency or frequency or cloudy urine, et cetera, you know, call us immediately. You may have this. We start you on antibiotics and you’re going to be OK.
Brian Brewer: Well, that’s good. We are almost out of time, but I do want to ask another question we’re getting from one of our viewers about resistance to immunotherapy. Can a patient respond well and then not respond, and then what happens?
Dr. Arjun Balar: Yeah. So, we do see this right. So eventually patients can, you know, patients can have a partial response or complete response, which means, you know, some of the cancer shrinks or sometimes it disappears completely, but then later on, it could relapse, and what that means is that, you know, a portion of the cancer develops what we call immune escape, and there are some, you know, really interesting studies that have shown that mutations such as in genes like JAK2 may be associated with it. You know, what that means is that we have much more work to do to understand what are the key other drugs or other checkpoints or other things that we need to do to address this, and that’s why we have clinical trials.
Brian Brewer: Well, you know, all we can say is thank you for doing what you do and for advancing the science through clinical research and looking at all the available data and just doing what we can do to get more bladder cancer patients to survive. So that is thank you so much. We have to wrap up. I’m so sorry if we weren’t able to get to the questions that you submitted, don’t worry, Dr. Balar will be sharing answers via the Cancer Research Institute blog. We will be sharing that information with you as well. So even if you have more questions, please continue to submit them and we’ll try our best to get to all of them. I also want to thank Perlmutter Cancer Institute at NYU Langone for its fantastic support of this event. You’re not only an excellent cancer treatment center, but you’re a great friend of Cancer Research Institute and helping us to get the word out about these important advances in immunotherapy treatment for bladder and many other types of cancer. So, thank you again for that, and finally, at the end of this session, you’ll see a poll pop up. We’d love to hear what you as a viewer got out of this presentation, and we want your feedback so that we can create the most valuable program for you going forward. Dr. Balar, thank you again. So much for your time and to all watching, thank you for joining us today at the second virtual CRI Cancer Immunotherapy Patient Summit. It is so wonderful to have all of you here with us.
Dr. Arjun Balar: Thanks for having me.