Setting the Stage for the BCG Unresponsive Population - Interview with Ashish Kamat
May 19, 2018
Ashish Kamat, MD, MPH and Alicia Morgans, MD discuss non-muscle invasive bladder cancer, where the field stands particularly for BCG refractory patients and the definition of the BCG unresponsive patient. Ashish overviews the efforts of the SUO-CTC Bladder Committee and important updates and trials in this disease state.
Biographies:
Ashish M. Kamat, MD
Alicia Morgans, MD, MPH
Further Related Content:
A Phase III, Open-Label Study to Evaluate the Safety and Efficacy of INSTILADRIN® (rAd-IFN)/Syn3) Administered Intravesically to Patients With High Grade, BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) - NCT02773849
Phase II Trial of Atezolizumab in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer - NCT02844816
Emerging Therapies for BCG-Unresponsive Non-muscle Invasive Bladder Cancer- EVERYDAY UROLOGY: Full Text article
Read the full video transcript
Dr. Alicia Morgans: Welcome to some further coverage from AUA 2018. I'm delighted to have with me Dr. Ashish Kamat, who is a professor of Urologic Oncology at the MD Anderson Cancer Center. Thanks so much for being here.
Dr. Ashish Kamat: Thank you for having me.
Dr. Alicia Morgans: So, I knew you've been doing a lot of work across Urologic Oncology. Many initiatives, but I really wanted to dig in with you about non-muscle invasive bladder cancer. Where that field stands particularly for those patients who are BCG refractory and get an understanding from your perspective of where that field is going and how we get there.
Dr. Ashish Kamat: Sure. Non-muscle invasive bladder cancer is you know, constitutes a large percentage of the patients that we have with bladder cancer, it's a large majority, about seventy-five percent. Traditionally for those patients that been such a mix match of treatments that we have offered them that's been hard to getting these drugs approved in, for example, the BCG unresponsive space that you just mentioned. For example, a drug that was approved in 1998 in this space, was approved barely eight or ten percent complete response rate in patients who failed BCG. Part of that really was because the endpoints were not well defined. So pharmaceutical companies that were sponsoring large trials or investigators who are designing trials really didn't know what bar they had to meet and there's a lot of failures reports coming out. People looking at the drugs and considering them not to have worked. So as part of a group effort, a group of us at GU ASCO several years ago actually came together and decided that we should interact with the FDA not just leave them off as an independent entity because obviously they too want to help our patients.
Through that effort, it was kind of a joint effort between the GU ASCO group as we call it, and then the International Bladder Cancer Group as well, which I lead to come up with certain guidelines, definitions, consensus statements really based on existent literature. And through that and to this joint effort, we came up with this new disease state when it comes to non-muscle bladder cancer which is BCG unresponsive. So traditionally when someone gets intravesical immunotherapy with BCG and they have a high-grade tumor recurrence as you know it’s called failure of BCG, which is true if you think about it. But how much BCG do they get? Do they get one installation, do they get six installations, do they get one year, do they get six months? Those variables have never really truly been accounted for when you look at patients who failed BCG. That's important because again a real clinical example is someone that gets six weeks of BCG with carcinoma in situ of the bladder and then at the first evaluation has persistent carcinoma in situ, has often been called a “BCG failure” and then he or she goes in a clinical trial. And then gets drug x and they have been 25-30% response rate which sounds great when you think about it, one and three responding to a drug but if you really look at the data, if those patients just got three more doses of BCG they’d have a 64% response rate.
So, you can salvage majority of patients with just three more courses of BCG. So, all of this kind of data came together and what we purposed and what the FDA actually in their memo that was finalized actually earlier this year have accepted this notion that there is a group of patients that are considered BCG unresponsive. If they received adequate BCG, and what is adequate BCG essentially, it’s once a week for six weeks so that the installation induction course of BCG followed by at least one course of maintenance and that should include at least two or three courses of BCG of installations. If patients get a little bit more, that's okay, but so long as they get this adequate BCG, and then they have a high recurrence, those patients are the highest risk of failure and those patients can then go on to clinical trials that are single-arm because there's no real comparative group.
So really when we talk about non-muscle bladder cancer that's a lot of work going on. I think this really is one of the most important developments we've had in the last eighteen months. It sounds sort of simple, but it is really important because its setting the stage for clean trials for clear cut entry criteria to be done moving forward.
Dr. Alicia Morgans: Absolutely, if we really don't have a homogenous population that's being studied, we can't really trust the outcomes that we see. If a patient was going to respond as simply getting a few additional doses of BCG and then responds to whatever experimental treatment we're giving that person is that really a success of the experimental treatment in a refractory population or is just an undertreated individual who responds to a treatment appropriately but doesn't necessarily reflect the population that you're studying so this is highly, highly important. I appreciate that you're setting the stage for these clinical trials. So, are there any studies that you're involved with now at MD Anderson looking at this BCG unresponsive population that you're enthusiastic about?
Dr. Ashish Kamat: This has become a very active space, I mean there's so much competition for trials in this space that its hard sometimes for us to actually say no because everyone's wanting to do trials in this arena. So, there's trials of single agent checkpoint inhibitors, Merck, AstraZeneca, Genentech. I mean there all running trials in single agent checkpoint inhibitor combinations in this arena but those are systemic agents so they have a little more toxicity profile. What we at MD Anderson and the SUO Clinical Trial Consortium have not necessary tried to limit but focus on is intravesical therapy. So, one of the trials that was actually developed through the MD Anderson SPORE starting almost ten years ago with preclinical work taking through phase one, phase two studies and ultimately now phase three studies through the leadership of our scientist Bill Benedict and PI Colin Dinney is our intravesical gene therapy trial.
So that's actually Nadofaragene firadenovec (Adstiladrin®) is the name that's given to it by the company now, FKD, but essentially, it’s an adenovirus interferon gene therapy instilled in bladder once, and then of course its transfected and then the bladder milieu itself produces interferon alpha, which then lasts for much longer than the repeated installations. In our phase two studies, that's published in JCO when Neal Shore was the first author on that for our group. It has a 35% durable response at a year plus, which was clearly meeting the bar that we purposed to the FDA what they accepted but better than anything else in the past as well. So that's now moved on to a phase three study.
Single arm, but it’s still called a phase three or allowed to be called a phase three because there's no true comparative arm, and I am pleased to let you know that we are just going to announce that this meeting, this week, that accrual is completed for this trial. Previous trials of similar nature took ten years to accrue. Just through group collaborative efforts, the SUO was very instrumental in this. We accrued 148 patients in barely two years and that's a really great achievement. Many of the trials in this space that we are excited about SWOG has studies that are being purposed is in different agents. It's a really busy space which is great for our patients.
Dr. Alicia Morgans: Absolutely and congratulations on meeting the accrual goals for that study that you just mentioned and the bladder population and general one of the challenges certainly in the advance disease but also in localized non-muscle invasive disease is, is really finding the patients who are willing to enroll and matching them with the right studies and that's been a problem in bladder cancer so wonderful that you've been able to meet that goal and I really look forward to the outcomes. Just to question about that study, how is that tolerated, you can image that if you're having local production that it might be, might be uncomfortable. Can you tell me a little bit about how patients are tolerating the treatment?
Dr. Ashish Kamat: So that's a very good question. I'm glad you asked that because its tolerated really, really well. Provided that the urologists or the treating physician recognizes some early nuances of the symptoms in the patient. And it really, to be honest with you, is something quite as simply as Aspirin, antispasmodics and a little bit of Tylenol, paracetamol simple measures allow the patient to tolerate the therapy really well so that we know about three or four grade toxicities, most of them are limiting and in fact after we recognized that you can symptomatically treat patients and take care of spasms and minor things like that, not a single patient had to stop therapy or has had an adverse event to a point where they can't tolerate the installation. The other in advantage of this therapy and I'm not just saying this because it's our study, but it really is good is that once every three-month dosing. So, it’s so much easier for our patients, lot of them are older, not had a good social support to come for every week installations or every two-week installation. They come once every three months and get a single installation, maybe wait in town they come from elsewhere for eight hours and then head back home. So it really is convenient and well tolerated.
Dr. Alicia Morgans: That's hugely important as we think about deploying new therapies to patients because so many patients travel a distance to have access to these therapies and being able to come once every three months and stay for a day, is much, much better for them, especially when they're coming from a distance and I'm certain that many of your patients are coming from a distance. Many of our patients set in Northwestern even if they're within the city it takes over an hour to get into the Cancer Center so this is hugely important for our patients and I am glad that you and your team recognize the importance of that. So, do you have any over-arching things, closing thoughts as we, I guess, kind of close this up for the listeners and viewers?
Dr. Ashish Kamat: The main thought that I want to put out there to listeners and viewers is that if you as a treating physician taking care some of the bladder cancer has a patient that has a high-risk disease, a high-grade non-muscle invasive bladder cancer, treat it very appropriately. You know we've come to this recognition when we were going through this whole process is that a large percentage of our patients in the country today are not getting adequate treatment. They're getting BCG immunotherapy and a very half asserted manner. Some people give two doses, some people give once a month, so the first message I want to set out is before you call your patient a BCG failure, or give them that label, make sure that they have been treated appropriately. That's bladder cancer 101 and after you're sure that the patient has indeed had a good trial of immunotherapy and it hasn't worked in the bladder, then please refer them for a clinical trial because that's how we get the next answer. If the patient doesn't qualify for a clinical trial, then we have many combination chemos that we can use off-label per se. But a well-controlled well-performed clinical trial will really help us advance this field and we have so many out there that there's no short of choices for the patient.
Dr. Alicia Morgans: Absolutely. So making sure that patients have adequate treatment upfront and are not called a failure just because we failed them essentially as physicians and then moving the field forward with further clinical trial enrollment, I think these are critical messages and that I appreciate it. Thank you so much for taking the time to speak with us today.
Dr. Ashish Kamat: Thank you.
Dr. Alicia Morgans: Welcome to some further coverage from AUA 2018. I'm delighted to have with me Dr. Ashish Kamat, who is a professor of Urologic Oncology at the MD Anderson Cancer Center. Thanks so much for being here.
Dr. Ashish Kamat: Thank you for having me.
Dr. Alicia Morgans: So, I knew you've been doing a lot of work across Urologic Oncology. Many initiatives, but I really wanted to dig in with you about non-muscle invasive bladder cancer. Where that field stands particularly for those patients who are BCG refractory and get an understanding from your perspective of where that field is going and how we get there.
Dr. Ashish Kamat: Sure. Non-muscle invasive bladder cancer is you know, constitutes a large percentage of the patients that we have with bladder cancer, it's a large majority, about seventy-five percent. Traditionally for those patients that been such a mix match of treatments that we have offered them that's been hard to getting these drugs approved in, for example, the BCG unresponsive space that you just mentioned. For example, a drug that was approved in 1998 in this space, was approved barely eight or ten percent complete response rate in patients who failed BCG. Part of that really was because the endpoints were not well defined. So pharmaceutical companies that were sponsoring large trials or investigators who are designing trials really didn't know what bar they had to meet and there's a lot of failures reports coming out. People looking at the drugs and considering them not to have worked. So as part of a group effort, a group of us at GU ASCO several years ago actually came together and decided that we should interact with the FDA not just leave them off as an independent entity because obviously they too want to help our patients.
Through that effort, it was kind of a joint effort between the GU ASCO group as we call it, and then the International Bladder Cancer Group as well, which I lead to come up with certain guidelines, definitions, consensus statements really based on existent literature. And through that and to this joint effort, we came up with this new disease state when it comes to non-muscle bladder cancer which is BCG unresponsive. So traditionally when someone gets intravesical immunotherapy with BCG and they have a high-grade tumor recurrence as you know it’s called failure of BCG, which is true if you think about it. But how much BCG do they get? Do they get one installation, do they get six installations, do they get one year, do they get six months? Those variables have never really truly been accounted for when you look at patients who failed BCG. That's important because again a real clinical example is someone that gets six weeks of BCG with carcinoma in situ of the bladder and then at the first evaluation has persistent carcinoma in situ, has often been called a “BCG failure” and then he or she goes in a clinical trial. And then gets drug x and they have been 25-30% response rate which sounds great when you think about it, one and three responding to a drug but if you really look at the data, if those patients just got three more doses of BCG they’d have a 64% response rate.
So, you can salvage majority of patients with just three more courses of BCG. So, all of this kind of data came together and what we purposed and what the FDA actually in their memo that was finalized actually earlier this year have accepted this notion that there is a group of patients that are considered BCG unresponsive. If they received adequate BCG, and what is adequate BCG essentially, it’s once a week for six weeks so that the installation induction course of BCG followed by at least one course of maintenance and that should include at least two or three courses of BCG of installations. If patients get a little bit more, that's okay, but so long as they get this adequate BCG, and then they have a high recurrence, those patients are the highest risk of failure and those patients can then go on to clinical trials that are single-arm because there's no real comparative group.
So really when we talk about non-muscle bladder cancer that's a lot of work going on. I think this really is one of the most important developments we've had in the last eighteen months. It sounds sort of simple, but it is really important because its setting the stage for clean trials for clear cut entry criteria to be done moving forward.
Dr. Alicia Morgans: Absolutely, if we really don't have a homogenous population that's being studied, we can't really trust the outcomes that we see. If a patient was going to respond as simply getting a few additional doses of BCG and then responds to whatever experimental treatment we're giving that person is that really a success of the experimental treatment in a refractory population or is just an undertreated individual who responds to a treatment appropriately but doesn't necessarily reflect the population that you're studying so this is highly, highly important. I appreciate that you're setting the stage for these clinical trials. So, are there any studies that you're involved with now at MD Anderson looking at this BCG unresponsive population that you're enthusiastic about?
Dr. Ashish Kamat: This has become a very active space, I mean there's so much competition for trials in this space that its hard sometimes for us to actually say no because everyone's wanting to do trials in this arena. So, there's trials of single agent checkpoint inhibitors, Merck, AstraZeneca, Genentech. I mean there all running trials in single agent checkpoint inhibitor combinations in this arena but those are systemic agents so they have a little more toxicity profile. What we at MD Anderson and the SUO Clinical Trial Consortium have not necessary tried to limit but focus on is intravesical therapy. So, one of the trials that was actually developed through the MD Anderson SPORE starting almost ten years ago with preclinical work taking through phase one, phase two studies and ultimately now phase three studies through the leadership of our scientist Bill Benedict and PI Colin Dinney is our intravesical gene therapy trial.
So that's actually Nadofaragene firadenovec (Adstiladrin®) is the name that's given to it by the company now, FKD, but essentially, it’s an adenovirus interferon gene therapy instilled in bladder once, and then of course its transfected and then the bladder milieu itself produces interferon alpha, which then lasts for much longer than the repeated installations. In our phase two studies, that's published in JCO when Neal Shore was the first author on that for our group. It has a 35% durable response at a year plus, which was clearly meeting the bar that we purposed to the FDA what they accepted but better than anything else in the past as well. So that's now moved on to a phase three study.
Single arm, but it’s still called a phase three or allowed to be called a phase three because there's no true comparative arm, and I am pleased to let you know that we are just going to announce that this meeting, this week, that accrual is completed for this trial. Previous trials of similar nature took ten years to accrue. Just through group collaborative efforts, the SUO was very instrumental in this. We accrued 148 patients in barely two years and that's a really great achievement. Many of the trials in this space that we are excited about SWOG has studies that are being purposed is in different agents. It's a really busy space which is great for our patients.
Dr. Alicia Morgans: Absolutely and congratulations on meeting the accrual goals for that study that you just mentioned and the bladder population and general one of the challenges certainly in the advance disease but also in localized non-muscle invasive disease is, is really finding the patients who are willing to enroll and matching them with the right studies and that's been a problem in bladder cancer so wonderful that you've been able to meet that goal and I really look forward to the outcomes. Just to question about that study, how is that tolerated, you can image that if you're having local production that it might be, might be uncomfortable. Can you tell me a little bit about how patients are tolerating the treatment?
Dr. Ashish Kamat: So that's a very good question. I'm glad you asked that because its tolerated really, really well. Provided that the urologists or the treating physician recognizes some early nuances of the symptoms in the patient. And it really, to be honest with you, is something quite as simply as Aspirin, antispasmodics and a little bit of Tylenol, paracetamol simple measures allow the patient to tolerate the therapy really well so that we know about three or four grade toxicities, most of them are limiting and in fact after we recognized that you can symptomatically treat patients and take care of spasms and minor things like that, not a single patient had to stop therapy or has had an adverse event to a point where they can't tolerate the installation. The other in advantage of this therapy and I'm not just saying this because it's our study, but it really is good is that once every three-month dosing. So, it’s so much easier for our patients, lot of them are older, not had a good social support to come for every week installations or every two-week installation. They come once every three months and get a single installation, maybe wait in town they come from elsewhere for eight hours and then head back home. So it really is convenient and well tolerated.
Dr. Alicia Morgans: That's hugely important as we think about deploying new therapies to patients because so many patients travel a distance to have access to these therapies and being able to come once every three months and stay for a day, is much, much better for them, especially when they're coming from a distance and I'm certain that many of your patients are coming from a distance. Many of our patients set in Northwestern even if they're within the city it takes over an hour to get into the Cancer Center so this is hugely important for our patients and I am glad that you and your team recognize the importance of that. So, do you have any over-arching things, closing thoughts as we, I guess, kind of close this up for the listeners and viewers?
Dr. Ashish Kamat: The main thought that I want to put out there to listeners and viewers is that if you as a treating physician taking care some of the bladder cancer has a patient that has a high-risk disease, a high-grade non-muscle invasive bladder cancer, treat it very appropriately. You know we've come to this recognition when we were going through this whole process is that a large percentage of our patients in the country today are not getting adequate treatment. They're getting BCG immunotherapy and a very half asserted manner. Some people give two doses, some people give once a month, so the first message I want to set out is before you call your patient a BCG failure, or give them that label, make sure that they have been treated appropriately. That's bladder cancer 101 and after you're sure that the patient has indeed had a good trial of immunotherapy and it hasn't worked in the bladder, then please refer them for a clinical trial because that's how we get the next answer. If the patient doesn't qualify for a clinical trial, then we have many combination chemos that we can use off-label per se. But a well-controlled well-performed clinical trial will really help us advance this field and we have so many out there that there's no short of choices for the patient.
Dr. Alicia Morgans: Absolutely. So making sure that patients have adequate treatment upfront and are not called a failure just because we failed them essentially as physicians and then moving the field forward with further clinical trial enrollment, I think these are critical messages and that I appreciate it. Thank you so much for taking the time to speak with us today.
Dr. Ashish Kamat: Thank you.