Update on Bladder Cancer, Current Trials and Treatments - Bishoy Faltas
June 24, 2018
(Length of Presentation: 10 min)
Alicia Morgans, MD and Bishoy Faltas, MD have an energetic conversation about the tremendous progress they have seen in the recent years in bladder cancer. Dr. Faltas takes us through some of the current research with IO therapy, specifically checkpoint inhibition; where they are currently used and where the clinical data may expand the use of these agents. He reviews relevant details of other targeted agents, as well as the value of detecting molecular alterations highlighting the ongoing trials and his vision for patients evolving to personalized medicine.
Biographies:
Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine.
Alicia Morgans, MD, MPH
Alicia Morgans, MD and Bishoy Faltas, MD have an energetic conversation about the tremendous progress they have seen in the recent years in bladder cancer. Dr. Faltas takes us through some of the current research with IO therapy, specifically checkpoint inhibition; where they are currently used and where the clinical data may expand the use of these agents. He reviews relevant details of other targeted agents, as well as the value of detecting molecular alterations highlighting the ongoing trials and his vision for patients evolving to personalized medicine.
Biographies:
Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine.
Alicia Morgans, MD, MPH
Read the full video transcript:
Dr. Alicia Morgans: Hi, and welcome to our ASCO 2018 coverage. I'm delighted to have here with me, Dr. Bishoy Faltas, who is an assistant professor of medicine at Weill Cornell Medicine at New York Presbyterian hospital. Thank you so much for being here with us today.
Dr. Bishoy Faltas: Thanks for having me.
Dr. Alicia Morgans: So, there's a lot going on at this year's ASCO, and a lot going on in general in the area of bladder cancer, and I'd love to hear your thoughts on new applications of immunotherapy in this space.
Dr. Bishoy Faltas: So yeah, thank you for this question. I think bladder cancer has really witnessed tremendous progress over the past few years, mainly in the area of immunotherapy and specifically immune checkpoint inhibition. We now have five agents that are approved in several settings, including the frontline setting in platinum ineligible patients, where some drugs are also approved. And now we're actually looking to expanding the use of these agents into different spaces. So for instance, there were some ongoing and planned clinical trials from several of my colleagues using immune checkpoint inhibition in the neoadjuvant setting, especially for patients who are platinum ineligible, who cannot receive one of the standards of care or the standard of care, which is neoadjuvant chemotherapy followed by a radical cystectomy. So this is a very exciting space and the results of these trials are eagerly awaited and would be very impactful.
Another space that is very exciting is actually moving immune checkpoint inhibition to other disease settings earlier in the natural history of the disease or different biological entities such as non-muscle invasive bladder cancer. So, there are different phase three trials that are ongoing or planned using immune checkpoint inhibitors in non-muscle invasive disease. There are also trials combining immunotherapy with chemoradiation to try to preserve bladders for patients with muscle-invasive disease. So a lot of exciting developments, potentially, if these results are positive, practice changing for the entire bladder cancer community.
Dr. Alicia Morgans: Very exciting. And I know there's development of a lot of other opportunities as well, so nonimmunotherapy based settings, and I'd love to hear your thoughts on those approaches and about any work you might be doing in the area as well.
Dr. Bishoy Faltas: So, thank you for that question too. So I think this is really what we need. Because at this point, even though we have five immune checkpoint inhibitors that are approved, we have chemotherapy, it is important to recognize that the majority of patients will not respond to one or the other. So we really need targeted agents in this space. And fortunately there's been a lot of advances in this area that are still very early, but it's very promising. One advance is, for instance, FGFR3 inhibitors and there was just a trial that was published a few days ago looking at an FGFR3 inhibitor in patients who have a FGFR3 alterations that showed a 25 percent response rate, which was very encouraging and a high disease control rate. So this is something that is very exciting.
There are other targeted agents. There was a compound called Rexahn 3117, which is also very promising. There was a poster presentation on this during this meeting. We are actually in the process of starting a clinical trial that will start very soon using cyclin-dependent kinase inhibitors, CDK4, the cyclin-dependent kinases four and six. This drug is called abemaciclib, which is actually FDA approved for patients with metastatic breast cancer. And this is based on some work that we've done in my laboratory looking at CDKN2A, which is in the pathway. It's upstream of CDK4 and CDK6, and nearly 25 to 40 percent of bladder cancer patients have deletions, copy number alterations, mainly deletions in the CDKN2A, which encodes for a protein called P16, which is upstream of CDK4 and CDK6. And we think that those patients will be sensitive to drugs like CDK4/6 inhibitors like abemaciclib.
So, we're starting actually a window of opportunity clinical trial for patients who are platinum ineligible and we're accruing a number of 20 patients that will receive abemaciclib for a period of four to eight weeks before they receive the radical cystectomy. We're very excited about this trial because every patient will have the tissue available from their transurethral resection of the bladder tumor that has done at the time of diagnosis and we will also have the tissue for comparison from their cystectomy and we were able to previously demonstrate that we're able to grow the tumors from patients with patient derived organoids. And this was published by us a couple of years ago and published recently by other groups in the New York area, showing that we can stably expand bladder cancer organoids in the laboratory.
So, this will allow us to do a co-clinical trial, testing the same drug and looking at the molecular determinants of sensitivity to abemaciclib in the laboratory. Something that is a very exciting and reflects also a new paradigm in terms of the window of opportunity clinical trials that I think we should expand more and more in bladder cancer.
Dr. Alicia Morgans: That's really exciting and it's an interesting space. So, the neoadjuvant space in a non-cisplatin eligible group of patients and you keep it very tight window, which is I think really important. Just to emphasize for everyone listening, you know, we usually try to get those patients to cystectomy as quickly as possible, but that's probably about the window of scheduling for your urologist, that four to six week period of time when you're administering the drugs. So really, it makes it not a delay of ... Ultimately, we would not want to delay surgery, I would think. So how does the treatment with this drug, at least in other settings where it's used, affect wound healing? Is this something that you expect should be not an issue, I would hope and think?
Dr. Bishoy Faltas: Yeah, we don't think. So, similar trials have been performed in a breast cancer patients.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: And we don't really think that this will affect wound healing. So that is not one of our safety considerations. It's actually a fairly well tolerated drug. There are actually two other CDK4/6 inhibitors that have been tried before in patients with metastatic breast cancer and they have slightly different toxicity profiles. The main toxicity of this drug is actually diarrhea. There were some cytopenias but they're not as severe as with palbociclib, which is another CDK4/6 inhibitor. So it's something that is very exciting, and as you very astutely mentioned, we definitely don't want to delay surgery, because surgery is the definitive treatment and hence the term "a window of opportunity", because while the patients are waiting for their cystectomy, instead of not getting anything, they will be getting a drug that is active and FDA approved in other cancers and that we have a very strong biological rationale to believe that it will also be active in patients with muscle invasive bladder cancer.
Dr. Alicia Morgans: Really exciting. And like you said, one of the most thrilling things will be that you'll be able to get that tissue and potentially grow these organoids and really test some of the more important biologic questions directly in those organized. So that'll be really wonderful. So, what else do you want to share with the listeners in this space? What other things are you excited about in the bladder cancer landscape right now?
Dr. Bishoy Faltas: So, the ultimate vision for patients with bladder cancer is really to be able to do precision medicine or precision oncology.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: Or personalized medicine where we can actually tailor the treatments to what every patient's tumor has, and order to do that, I think there are a lot of components for this. One component, as you mentioned are the patient derived organoids, which really allows us to test these many avatars, can be tested for all these different treatments and can be observed also for their development of resistance over time. So, this concept of a co-clinical trial is something that we're really excited about and that would hopefully play a role in achieving this vision. The other component of that is the ability to be able to follow someone's cancer over time, because from my work and others, we know that bladder cancers are very heterogeneous. We know that they evolve over time. We know that two different metastatic lesions from the same patient would not share the majority of mutations, over 70 percent of the mutations are actually not shared. And in order to capture this tremendous heterogeneity, this full arc of the evolution of the tumor, we need new technology.
Something that's very exciting nowadays is circulating tumor DNA technology. There was an abstract during this meeting that was part of a major team that we participated in, a team effort that we participated in, and we can demonstrate that we could actually detect molecular alterations that are very similar to what we observed in the primary tumors. And we hope that in the future to show that we can use this technology to follow patients during their treatment course.
Dr. Alicia Morgans: That's really exciting and I appreciate that you're doing this work from myself and from all of the patients who I think will really benefit over time. So, do you have any closing thoughts or overarching themes, messages to the viewers?
Dr. Bishoy Faltas: So, the main thing is I think we need more research in bladder cancer.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: I think it's an area that has been neglected for many years, up until recently. I'm very glad that there is excitement and there is momentum in this space.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: I hope it's not only restricted to immunotherapy, but also expands to other areas similar to what you and I discussed today.
Dr. Alicia Morgans: Yes, agreed. You know, it's a lot more than just immunotherapy where response rates are still in the 24, 28 percent range. We need to do better for these patients and your efforts at molecular characterization and really putting the right patient with the right treatment, I think are really what we need to move the field forward. So thank you so much.
Dr. Bishoy Faltas: Thank you.
Dr. Alicia Morgans: Hi, and welcome to our ASCO 2018 coverage. I'm delighted to have here with me, Dr. Bishoy Faltas, who is an assistant professor of medicine at Weill Cornell Medicine at New York Presbyterian hospital. Thank you so much for being here with us today.
Dr. Bishoy Faltas: Thanks for having me.
Dr. Alicia Morgans: So, there's a lot going on at this year's ASCO, and a lot going on in general in the area of bladder cancer, and I'd love to hear your thoughts on new applications of immunotherapy in this space.
Dr. Bishoy Faltas: So yeah, thank you for this question. I think bladder cancer has really witnessed tremendous progress over the past few years, mainly in the area of immunotherapy and specifically immune checkpoint inhibition. We now have five agents that are approved in several settings, including the frontline setting in platinum ineligible patients, where some drugs are also approved. And now we're actually looking to expanding the use of these agents into different spaces. So for instance, there were some ongoing and planned clinical trials from several of my colleagues using immune checkpoint inhibition in the neoadjuvant setting, especially for patients who are platinum ineligible, who cannot receive one of the standards of care or the standard of care, which is neoadjuvant chemotherapy followed by a radical cystectomy. So this is a very exciting space and the results of these trials are eagerly awaited and would be very impactful.
Another space that is very exciting is actually moving immune checkpoint inhibition to other disease settings earlier in the natural history of the disease or different biological entities such as non-muscle invasive bladder cancer. So, there are different phase three trials that are ongoing or planned using immune checkpoint inhibitors in non-muscle invasive disease. There are also trials combining immunotherapy with chemoradiation to try to preserve bladders for patients with muscle-invasive disease. So a lot of exciting developments, potentially, if these results are positive, practice changing for the entire bladder cancer community.
Dr. Alicia Morgans: Very exciting. And I know there's development of a lot of other opportunities as well, so nonimmunotherapy based settings, and I'd love to hear your thoughts on those approaches and about any work you might be doing in the area as well.
Dr. Bishoy Faltas: So, thank you for that question too. So I think this is really what we need. Because at this point, even though we have five immune checkpoint inhibitors that are approved, we have chemotherapy, it is important to recognize that the majority of patients will not respond to one or the other. So we really need targeted agents in this space. And fortunately there's been a lot of advances in this area that are still very early, but it's very promising. One advance is, for instance, FGFR3 inhibitors and there was just a trial that was published a few days ago looking at an FGFR3 inhibitor in patients who have a FGFR3 alterations that showed a 25 percent response rate, which was very encouraging and a high disease control rate. So this is something that is very exciting.
There are other targeted agents. There was a compound called Rexahn 3117, which is also very promising. There was a poster presentation on this during this meeting. We are actually in the process of starting a clinical trial that will start very soon using cyclin-dependent kinase inhibitors, CDK4, the cyclin-dependent kinases four and six. This drug is called abemaciclib, which is actually FDA approved for patients with metastatic breast cancer. And this is based on some work that we've done in my laboratory looking at CDKN2A, which is in the pathway. It's upstream of CDK4 and CDK6, and nearly 25 to 40 percent of bladder cancer patients have deletions, copy number alterations, mainly deletions in the CDKN2A, which encodes for a protein called P16, which is upstream of CDK4 and CDK6. And we think that those patients will be sensitive to drugs like CDK4/6 inhibitors like abemaciclib.
So, we're starting actually a window of opportunity clinical trial for patients who are platinum ineligible and we're accruing a number of 20 patients that will receive abemaciclib for a period of four to eight weeks before they receive the radical cystectomy. We're very excited about this trial because every patient will have the tissue available from their transurethral resection of the bladder tumor that has done at the time of diagnosis and we will also have the tissue for comparison from their cystectomy and we were able to previously demonstrate that we're able to grow the tumors from patients with patient derived organoids. And this was published by us a couple of years ago and published recently by other groups in the New York area, showing that we can stably expand bladder cancer organoids in the laboratory.
So, this will allow us to do a co-clinical trial, testing the same drug and looking at the molecular determinants of sensitivity to abemaciclib in the laboratory. Something that is a very exciting and reflects also a new paradigm in terms of the window of opportunity clinical trials that I think we should expand more and more in bladder cancer.
Dr. Alicia Morgans: That's really exciting and it's an interesting space. So, the neoadjuvant space in a non-cisplatin eligible group of patients and you keep it very tight window, which is I think really important. Just to emphasize for everyone listening, you know, we usually try to get those patients to cystectomy as quickly as possible, but that's probably about the window of scheduling for your urologist, that four to six week period of time when you're administering the drugs. So really, it makes it not a delay of ... Ultimately, we would not want to delay surgery, I would think. So how does the treatment with this drug, at least in other settings where it's used, affect wound healing? Is this something that you expect should be not an issue, I would hope and think?
Dr. Bishoy Faltas: Yeah, we don't think. So, similar trials have been performed in a breast cancer patients.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: And we don't really think that this will affect wound healing. So that is not one of our safety considerations. It's actually a fairly well tolerated drug. There are actually two other CDK4/6 inhibitors that have been tried before in patients with metastatic breast cancer and they have slightly different toxicity profiles. The main toxicity of this drug is actually diarrhea. There were some cytopenias but they're not as severe as with palbociclib, which is another CDK4/6 inhibitor. So it's something that is very exciting, and as you very astutely mentioned, we definitely don't want to delay surgery, because surgery is the definitive treatment and hence the term "a window of opportunity", because while the patients are waiting for their cystectomy, instead of not getting anything, they will be getting a drug that is active and FDA approved in other cancers and that we have a very strong biological rationale to believe that it will also be active in patients with muscle invasive bladder cancer.
Dr. Alicia Morgans: Really exciting. And like you said, one of the most thrilling things will be that you'll be able to get that tissue and potentially grow these organoids and really test some of the more important biologic questions directly in those organized. So that'll be really wonderful. So, what else do you want to share with the listeners in this space? What other things are you excited about in the bladder cancer landscape right now?
Dr. Bishoy Faltas: So, the ultimate vision for patients with bladder cancer is really to be able to do precision medicine or precision oncology.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: Or personalized medicine where we can actually tailor the treatments to what every patient's tumor has, and order to do that, I think there are a lot of components for this. One component, as you mentioned are the patient derived organoids, which really allows us to test these many avatars, can be tested for all these different treatments and can be observed also for their development of resistance over time. So, this concept of a co-clinical trial is something that we're really excited about and that would hopefully play a role in achieving this vision. The other component of that is the ability to be able to follow someone's cancer over time, because from my work and others, we know that bladder cancers are very heterogeneous. We know that they evolve over time. We know that two different metastatic lesions from the same patient would not share the majority of mutations, over 70 percent of the mutations are actually not shared. And in order to capture this tremendous heterogeneity, this full arc of the evolution of the tumor, we need new technology.
Something that's very exciting nowadays is circulating tumor DNA technology. There was an abstract during this meeting that was part of a major team that we participated in, a team effort that we participated in, and we can demonstrate that we could actually detect molecular alterations that are very similar to what we observed in the primary tumors. And we hope that in the future to show that we can use this technology to follow patients during their treatment course.
Dr. Alicia Morgans: That's really exciting and I appreciate that you're doing this work from myself and from all of the patients who I think will really benefit over time. So, do you have any closing thoughts or overarching themes, messages to the viewers?
Dr. Bishoy Faltas: So, the main thing is I think we need more research in bladder cancer.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: I think it's an area that has been neglected for many years, up until recently. I'm very glad that there is excitement and there is momentum in this space.
Dr. Alicia Morgans: Yes.
Dr. Bishoy Faltas: I hope it's not only restricted to immunotherapy, but also expands to other areas similar to what you and I discussed today.
Dr. Alicia Morgans: Yes, agreed. You know, it's a lot more than just immunotherapy where response rates are still in the 24, 28 percent range. We need to do better for these patients and your efforts at molecular characterization and really putting the right patient with the right treatment, I think are really what we need to move the field forward. So thank you so much.
Dr. Bishoy Faltas: Thank you.