From Dismal to Promising: Discoveries Transforming Treatment Options for Advanced Urothelial Carcinoma - Shilpa Gupta
January 27, 2023
Sam Chang welcomes Shilpa Gupta to discuss the evolving treatment paradigm for advanced urothelial carcinoma, focusing particularly on platinum eligibility for patients. Dr. Gupta traces the progression of treatments, from gemcitabine and carboplatin prior to 2017 to the introduction of two checkpoint inhibitors, atezolizumab and pembrolizumab, in 2017. However, she notes the shift back to platinum treatments, augmented by immunotherapy maintenance, following concerning results from trials. Dr. Gupta emphasizes the importance of correctly determining a patient's eligibility for platinum treatments, sharing findings from surveys of medical oncologists that helped to define clearer criteria. Both speakers emphasize the need for consistency in patient selection to facilitate more meaningful comparisons in future trials. Dr. Gupta is hopeful that this work will lead to better treatment allocation, avoiding unnecessary declarations of platinum-ineligibility.
Biographies:
Shilpa Gupta, MD, Director, Genitourinary Medical Oncology, Taussig Cancer Institute, Co-Leader of the Genitourinary Oncology Program, Cleveland Clinic, Cleveland, OH
Sam S. Chang, MD, MBA, Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center
Biographies:
Shilpa Gupta, MD, Director, Genitourinary Medical Oncology, Taussig Cancer Institute, Co-Leader of the Genitourinary Oncology Program, Cleveland Clinic, Cleveland, OH
Sam S. Chang, MD, MBA, Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center
Read the Full Video Transcript
Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt. We are very fortunate today to have Dr. Shilpa Gupta. Shilpa is a superstar in medical oncology and has many hats. She is in fact the Director of GU Medical Oncology at the Taussig Institute. At Cleveland Clinic, she's also the Co-Director of their GU Medical Oncology Program. I've had the pleasure of knowing Shilpa for some time as she has led efforts for different types of therapies when it comes to advanced urothelial carcinoma. And so, we've asked her today to focus on the evolving paradigm, and definition, and evaluation of what a patient is defined in terms of platinum eligibility. That becomes important more and more in these days as we have different options for patients in terms of what we can give them, what we can offer them, and what, perhaps, we can evaluate in the future in clinical trials. So Shilpa, thank you again so much for presenting today, and I think you've got some slides to share with us.
Shilpa Gupta: Thank you, Sam, for the nice introduction. Really honored to discuss this endeavor with you. So Sam, as you mentioned, the treatment paradigm has evolved a lot over the last several years for patients who are not eligible to receive Cisplatin. These metastatic urothelial cancer patients in the past, gemcitabine and carboplatin is what we had prior to 2017. The outcomes were pretty dismal, with response rates only in mid-thirties, ORR survival only about nine months. Then, in summer of 2017, we had two checkpoint inhibitors approved as frontline therapy based on single arm trials.
The IMvigor 210 showed that atezolizumab led to overall survival of close to 16 months and really remarkable duration of response. The KEYNOTE-052 study showed pembrolizumab also led to really very impressive duration of response, as well as response rates of 25% or so. This led to accelerated FDA approval of these two agents. This is what we were using up until June 2018, when interim analysis from phase three trials of atezolizumab and pembrolizumab being compared to gem-carbo showed that patients who received single agent immunotherapy actually did worse. They were deaths, and FDA led to this announcement for label restriction to only those patients whose tumors were expressing high PD-L1, or those who were platinum-ineligible.
Because in the early data, they saw that there were early deaths with immunotherapy compared to gem-carbo. Then, we had the phase three JAVELIN Bladder 100 trial where gem-carbo followed by avelumab maintenance showed improvement in overall survival by around seven months, compared to best supportive care. This has now become the level one evidence for the new standard of care and was approved in 2020. More recently, in August 2021, FDA further restricted the label of pembrolizumab to only platinum-ineligible patients, regardless of PD-L1 expression. This was after the FDA would act meeting in August 2021.
As of now, the standard of care is gem-carbo followed by avelumab maintenance. However, defining platinum-ineligibility was not... which we were used to before, because we only thought of patients as cisplatin-eligible or cisplatin-ineligible, never really the question of carboplatin inability came around. So back in 2018, after the initial label restriction, we got together as a group and decided to get a survey going to see what folks who treat bladder cancer patients, medical oncologists in the U.S. This was actually conceived at a beacon meeting at the time.
So we sent out this survey to our several questions as to what would be the threshold for providers to not use carboplatin, and this was a new concept. These were the questions which we asked at the time, like creatinine clearance, like sixties, the kind of platin, we gave variety of options for carboplatin. We asked about age, even advanced age, like over 90 years, we asked what equal performance status they consider as their threshold. We also asked about peripheral neuropathy and heart failure. These questions, which we routinely use for determining how free patients are.
We found that creatinine clearance of less than 30 was the most chosen option. Age did not make a difference. Hearing loss also did not make a difference. ECOG performance status three or higher was when medical oncologists thought they would not give carboplatin. Peripheral neuropathy grade three or higher or heart failure class three or higher. We proposed this at the time, and one of these criteria as being a rough guide to aid clinical decision-making. In an ECOG performance status of two, patient with that kind of performance status, also creatinine clearance less than 30 was the cutoff. We specifically asked this question because... And initially URTC study showed that patients who have ECOG performance status two, and creatinine clearance less than 60, they do poorly with carboplatin.
In this, we specifically asked that question, and the response was still that the cutoff would be less than 30, and people would still use carboplatin. Now given that the landscape has changed so rapidly, we decided to send out the same survey with some additional questions to a similar cohort of 60 medical oncologists in the US, and we also asked them if they're using gem carbo followed by avelumab or pembrolizumab, not level one evidence, but there's a phase two trial for maintenance setting, or also whether folks are testing for PD-L1 status before using immunotherapy. We found that all medical oncologists were using maintenance immunotherapy. 94% were using avelumab based on the level one evidence, and only about 28% medical oncologists were checking for PD-L1 status before using pembrolizumab. About half of them were still checking for PD-L1 prior to using atezolizumab because that label still stands for high PD-L1 subgroup.
We sent out the same questions as before, and we found that the responses were well-maintained. ECOG performance status greater than or equal to three creatinine clearance, less than 30. Peripheral neuropathy, this time, it was swinging a little bit towards grade two or higher. As you can see, 48% folks thought grade two or higher is the cutoff for not using carbo, and 42% patient providers thought it was grade three or higher. So neuropathy grade two or higher is what we really proposed this time and heart failure. And again, ECOG performance status two and creatinine clearance less than 30. This is a rough guide to primarily avoid over calling of platinum-ineligibility. When possible, give platinums. And also, hopefully, to standardize the eligibility criteria for trials moving forward. This was the results from the survey, and now, I'll stop sharing my screen.
Sam Chang: Shilpa, that was great. I think I'm going to start off in terms of questions with one of the latter statements that you made to actually be careful of not calling too many patients platinum-ineligible. I think early on, perhaps, there was a tendency to discount patients from chemotherapy and to try one of these new immunotherapeutic agents. But I think with the more recent studies, at least from a surgeon standpoint, there's been... I think I've sensed the shift back to understanding that platinum really still plays an important role in patients with advanced urothelial carcinoma, is that your take as well?
Shilpa Gupta: Yes, certainly, Sam. Based on the data, we have seen a full circle back to platinums followed by immunotherapy maintenance now. I think that is what we have started using as a group and trying to raise awareness, not to deem people unnecessarily platinum-ineligible.
Sam Chang: So when looking at that, in terms of the criteria for those, how was this information being kind of transmitted to our colleagues in practice and those who don't see as much advance urothelial carcinoma. How are you all spreading this message around?
Shilpa Gupta: That's a great question, Sam. So we have presented this at ASCO this year, and right now, we are writing the consensus criteria. We'll get the paper out soon, so there's more widespread awareness. We have also now launched this endeavor in European countries, where they will do a much larger survey for their physicians in different practices. Some countries, surgeons do give immunotherapy and other systemic therapy. So that process is ongoing to get a more global view on this. We are also looking at some real-world data using Flatiron database and getting that information out. Outcomes based on platinum in eligibility if we use this criteria.
Lastly, moving forward, thinking the next step is to define trials for such patients. So we are working on designing trials with innovative agents as frontline therapy using adaptation of these criteria. For example, here, creatinine clearance of 30 is what the cut off was. For trials, just to be more safe, we've kept it a little generous, like 40. At least not offering these treatments to patients who can easily get carboplatin. That's the goal. I think moving forward that is really the hope, that we can offer the right treatment to patients without deeming them ineligible.
Sam Chang: Yeah. I think that establishing criteria like that for consistency, I think, will be really beneficial as we move forward. Just as you say, just to allow the comparison of apples to apples and oranges to oranges. All right. Let me ask you a tougher question here. One that probably doesn't have a right or wrong answer. This clearly seems to apply, in terms of this eligibility, with the data, for those patients with advanced and metastatic urothelial carcinoma.
Obviously, we've had some studies done or being currently done in the neoadjuvant setting. And, in the neoadjuvant setting, it seems that our cisplatin, either GemCis or our dose-dense MVAC regimens, have shown a benefit in the neoadjuvant setting. We're looking at trials now for immunotherapy, combination therapies in the neoadjuvant setting. Do you think this platinum eligibility criteria for immunotherapy or other agents is going to be applied in the neoadjuvant setting?
Shilpa Gupta: That's a great question, Sam. I think if you look at these criteria, these patients are... Some people might argue that these patients probably are too free to receive anything. Why not just not offer anything or do just supportive care? I think the question would be to build the surgical fitness around those, to see if such a patient is seen by you or urologists who do cystectomies, would they like to operate on them? I think those criteria, really, it's very important because, Sam, as you know, in the real world, we do see these patients who undergo surgery. And then, they really have poor outcomes only because of how they were preoperatively. I think that we should still work on and determine if this goes hand in hand with surgical fitness.
Sam Chang: Yeah, no, I think that point's essential. Attempting to define that, those group of patients, both before surgery and after surgery, I think, is really essential and really important. But I applaud your efforts, Shilpa, so much in attempt to better define the patient population that gets benefit from treatment that probably, they can receive and can receive safely. And that has been shown, just as you say, compared to standard of care, to actually improve and lengthen survival. I think that data is, I think, quite persuasive.
And so, Shilpa, thanks so much for better defining and giving us an idea of the appropriate patient populations in terms of therapy. I look forward to the manuscript, and I also look forward to... This is the first time I heard about having our international colleagues also actually contribute in terms of their practice patterns, and what they would consider to be beneficial for our patients. So thanks again, Shilpa. I look forward to seeing you soon again in-person and also doing another one of these sessions together as well.
Shilpa Gupta: Thank you, Sam. This was great, and thanks for the opportunity, as always. Have a great day.
Sam Chang: Great. Thanks.
Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt. We are very fortunate today to have Dr. Shilpa Gupta. Shilpa is a superstar in medical oncology and has many hats. She is in fact the Director of GU Medical Oncology at the Taussig Institute. At Cleveland Clinic, she's also the Co-Director of their GU Medical Oncology Program. I've had the pleasure of knowing Shilpa for some time as she has led efforts for different types of therapies when it comes to advanced urothelial carcinoma. And so, we've asked her today to focus on the evolving paradigm, and definition, and evaluation of what a patient is defined in terms of platinum eligibility. That becomes important more and more in these days as we have different options for patients in terms of what we can give them, what we can offer them, and what, perhaps, we can evaluate in the future in clinical trials. So Shilpa, thank you again so much for presenting today, and I think you've got some slides to share with us.
Shilpa Gupta: Thank you, Sam, for the nice introduction. Really honored to discuss this endeavor with you. So Sam, as you mentioned, the treatment paradigm has evolved a lot over the last several years for patients who are not eligible to receive Cisplatin. These metastatic urothelial cancer patients in the past, gemcitabine and carboplatin is what we had prior to 2017. The outcomes were pretty dismal, with response rates only in mid-thirties, ORR survival only about nine months. Then, in summer of 2017, we had two checkpoint inhibitors approved as frontline therapy based on single arm trials.
The IMvigor 210 showed that atezolizumab led to overall survival of close to 16 months and really remarkable duration of response. The KEYNOTE-052 study showed pembrolizumab also led to really very impressive duration of response, as well as response rates of 25% or so. This led to accelerated FDA approval of these two agents. This is what we were using up until June 2018, when interim analysis from phase three trials of atezolizumab and pembrolizumab being compared to gem-carbo showed that patients who received single agent immunotherapy actually did worse. They were deaths, and FDA led to this announcement for label restriction to only those patients whose tumors were expressing high PD-L1, or those who were platinum-ineligible.
Because in the early data, they saw that there were early deaths with immunotherapy compared to gem-carbo. Then, we had the phase three JAVELIN Bladder 100 trial where gem-carbo followed by avelumab maintenance showed improvement in overall survival by around seven months, compared to best supportive care. This has now become the level one evidence for the new standard of care and was approved in 2020. More recently, in August 2021, FDA further restricted the label of pembrolizumab to only platinum-ineligible patients, regardless of PD-L1 expression. This was after the FDA would act meeting in August 2021.
As of now, the standard of care is gem-carbo followed by avelumab maintenance. However, defining platinum-ineligibility was not... which we were used to before, because we only thought of patients as cisplatin-eligible or cisplatin-ineligible, never really the question of carboplatin inability came around. So back in 2018, after the initial label restriction, we got together as a group and decided to get a survey going to see what folks who treat bladder cancer patients, medical oncologists in the U.S. This was actually conceived at a beacon meeting at the time.
So we sent out this survey to our several questions as to what would be the threshold for providers to not use carboplatin, and this was a new concept. These were the questions which we asked at the time, like creatinine clearance, like sixties, the kind of platin, we gave variety of options for carboplatin. We asked about age, even advanced age, like over 90 years, we asked what equal performance status they consider as their threshold. We also asked about peripheral neuropathy and heart failure. These questions, which we routinely use for determining how free patients are.
We found that creatinine clearance of less than 30 was the most chosen option. Age did not make a difference. Hearing loss also did not make a difference. ECOG performance status three or higher was when medical oncologists thought they would not give carboplatin. Peripheral neuropathy grade three or higher or heart failure class three or higher. We proposed this at the time, and one of these criteria as being a rough guide to aid clinical decision-making. In an ECOG performance status of two, patient with that kind of performance status, also creatinine clearance less than 30 was the cutoff. We specifically asked this question because... And initially URTC study showed that patients who have ECOG performance status two, and creatinine clearance less than 60, they do poorly with carboplatin.
In this, we specifically asked that question, and the response was still that the cutoff would be less than 30, and people would still use carboplatin. Now given that the landscape has changed so rapidly, we decided to send out the same survey with some additional questions to a similar cohort of 60 medical oncologists in the US, and we also asked them if they're using gem carbo followed by avelumab or pembrolizumab, not level one evidence, but there's a phase two trial for maintenance setting, or also whether folks are testing for PD-L1 status before using immunotherapy. We found that all medical oncologists were using maintenance immunotherapy. 94% were using avelumab based on the level one evidence, and only about 28% medical oncologists were checking for PD-L1 status before using pembrolizumab. About half of them were still checking for PD-L1 prior to using atezolizumab because that label still stands for high PD-L1 subgroup.
We sent out the same questions as before, and we found that the responses were well-maintained. ECOG performance status greater than or equal to three creatinine clearance, less than 30. Peripheral neuropathy, this time, it was swinging a little bit towards grade two or higher. As you can see, 48% folks thought grade two or higher is the cutoff for not using carbo, and 42% patient providers thought it was grade three or higher. So neuropathy grade two or higher is what we really proposed this time and heart failure. And again, ECOG performance status two and creatinine clearance less than 30. This is a rough guide to primarily avoid over calling of platinum-ineligibility. When possible, give platinums. And also, hopefully, to standardize the eligibility criteria for trials moving forward. This was the results from the survey, and now, I'll stop sharing my screen.
Sam Chang: Shilpa, that was great. I think I'm going to start off in terms of questions with one of the latter statements that you made to actually be careful of not calling too many patients platinum-ineligible. I think early on, perhaps, there was a tendency to discount patients from chemotherapy and to try one of these new immunotherapeutic agents. But I think with the more recent studies, at least from a surgeon standpoint, there's been... I think I've sensed the shift back to understanding that platinum really still plays an important role in patients with advanced urothelial carcinoma, is that your take as well?
Shilpa Gupta: Yes, certainly, Sam. Based on the data, we have seen a full circle back to platinums followed by immunotherapy maintenance now. I think that is what we have started using as a group and trying to raise awareness, not to deem people unnecessarily platinum-ineligible.
Sam Chang: So when looking at that, in terms of the criteria for those, how was this information being kind of transmitted to our colleagues in practice and those who don't see as much advance urothelial carcinoma. How are you all spreading this message around?
Shilpa Gupta: That's a great question, Sam. So we have presented this at ASCO this year, and right now, we are writing the consensus criteria. We'll get the paper out soon, so there's more widespread awareness. We have also now launched this endeavor in European countries, where they will do a much larger survey for their physicians in different practices. Some countries, surgeons do give immunotherapy and other systemic therapy. So that process is ongoing to get a more global view on this. We are also looking at some real-world data using Flatiron database and getting that information out. Outcomes based on platinum in eligibility if we use this criteria.
Lastly, moving forward, thinking the next step is to define trials for such patients. So we are working on designing trials with innovative agents as frontline therapy using adaptation of these criteria. For example, here, creatinine clearance of 30 is what the cut off was. For trials, just to be more safe, we've kept it a little generous, like 40. At least not offering these treatments to patients who can easily get carboplatin. That's the goal. I think moving forward that is really the hope, that we can offer the right treatment to patients without deeming them ineligible.
Sam Chang: Yeah. I think that establishing criteria like that for consistency, I think, will be really beneficial as we move forward. Just as you say, just to allow the comparison of apples to apples and oranges to oranges. All right. Let me ask you a tougher question here. One that probably doesn't have a right or wrong answer. This clearly seems to apply, in terms of this eligibility, with the data, for those patients with advanced and metastatic urothelial carcinoma.
Obviously, we've had some studies done or being currently done in the neoadjuvant setting. And, in the neoadjuvant setting, it seems that our cisplatin, either GemCis or our dose-dense MVAC regimens, have shown a benefit in the neoadjuvant setting. We're looking at trials now for immunotherapy, combination therapies in the neoadjuvant setting. Do you think this platinum eligibility criteria for immunotherapy or other agents is going to be applied in the neoadjuvant setting?
Shilpa Gupta: That's a great question, Sam. I think if you look at these criteria, these patients are... Some people might argue that these patients probably are too free to receive anything. Why not just not offer anything or do just supportive care? I think the question would be to build the surgical fitness around those, to see if such a patient is seen by you or urologists who do cystectomies, would they like to operate on them? I think those criteria, really, it's very important because, Sam, as you know, in the real world, we do see these patients who undergo surgery. And then, they really have poor outcomes only because of how they were preoperatively. I think that we should still work on and determine if this goes hand in hand with surgical fitness.
Sam Chang: Yeah, no, I think that point's essential. Attempting to define that, those group of patients, both before surgery and after surgery, I think, is really essential and really important. But I applaud your efforts, Shilpa, so much in attempt to better define the patient population that gets benefit from treatment that probably, they can receive and can receive safely. And that has been shown, just as you say, compared to standard of care, to actually improve and lengthen survival. I think that data is, I think, quite persuasive.
And so, Shilpa, thanks so much for better defining and giving us an idea of the appropriate patient populations in terms of therapy. I look forward to the manuscript, and I also look forward to... This is the first time I heard about having our international colleagues also actually contribute in terms of their practice patterns, and what they would consider to be beneficial for our patients. So thanks again, Shilpa. I look forward to seeing you soon again in-person and also doing another one of these sessions together as well.
Shilpa Gupta: Thank you, Sam. This was great, and thanks for the opportunity, as always. Have a great day.
Sam Chang: Great. Thanks.