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Choosing Frontline Therapy for Metastatic Kidney Cancer

Panelists: Robert A. Figlin, MD, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center; Eric Jonasch, MD, University of Texas MD Anderson Cancer Center; Toni K. Choueiri, MD, Dana-Farber Cancer Institute; Michael R. Harrison, MD, Duke Cancer Institute; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published: Monday, Mar 27, 2017



Transcript:

Robert A. Figlin, MD:
Toni, let me give you a few scenarios that I’d like for you to comment on because we see them in the office. A patient presents with a primary tumor in place with metastatic disease. So, what are your comments about cytoreductive nephrectomy in that setting? And then, once the decision is made on whether it’s been active surveillance or the patient is developing symptoms, you want to initiate therapy, what is your thought process for initiating therapy and the choice of agents?

Toni K. Choueiri, MD: The first question, going back, as a patient presents with kidney in place, is this patient eligible for a cytoreductive nephrectomy? Usually I try, if they’re eligible for cytoreductive nephrectomy, to get it out of the way initially. It does provide, in the appropriate clinical context, a survival benefit. I cannot say this is a level 1 evidence yet because there are trials ongoing. That may not actually answer the question, trials over 10 years slowly accruing that are ongoing, but at least, if you look retrospectively at retrospective studies as well as large national data set, there is a survival benefit from cytoreductive therapy in patients with limited disease burden and good performance status who can go to the operating room—so a lot of common sense. I try to get this out of the way, and it’s important because you will get additional information from a kidney that is removed that you may not be able to get from a biopsy, especially if a fine needle aspiration is done, that shows you general renal cell carcinoma. So, after that, and the patient is symptomatic, we need to start the treatment pretty quickly. I give usually around 2 weeks at least for the healing, sometimes more, especially if we have a clinical trial. And we start with a VEGF-targeted therapy normally.

Now our thought from almost 10 years ago about using temsirolimus in patients with poor-risk criteria, at least patients that present with metastatic disease with kidney in place have one criteria, so they’re at least intermediate. One more will make you poor at least, or 2 more per the Hudes criteria. But the problem with this is that this is an intravenous infusion weekly that is associated with a lower response rate, where in the clinical trial, the control arm was interferon. Retrospectively, several VEGF-targeted treatments showed efficacy in several subsets with poor-risk disease. So, if the patient is hospitalized, not doing well, you want to start the treatment and you want to start it fast—a quick prescription—then you start with temsirolimus. But, if you’re managing this patient as an outpatient, you have the time to start with an oral VEGF-targeted agent.

Robert A. Figlin, MD: Just to push you a little bit, Toni, there are patients where the primary tumor is there. Sometimes the extent of metastatic disease is greater than the volume of disease in the kidney. Sometimes the patient’s symptoms are not from the primary tumor, but from their metastatic disease. I just want to be clear, are there populations of patients where you think initiation of systemic therapy without cytoreductive therapy is an acceptable approach?

Toni K. Choueiri, MD: Absolutely, and those are the patients where you need to start systemic therapy and perhaps think about cytoreductive nephrectomy later. And sometimes, especially if you usually get single-agent, it’s rare to have an amazing response in the primary, but we don’t know. Perhaps with a novel combination, we don’t need any more cytoreductive nephrectomy. So, absolutely in these situations, systemic therapy is needed.

Robert A. Figlin, MD: Eric, we’re faced with the patient that Toni just described. The patients had their cytoreductive nephrectomy if appropriate. They’ve not had it if they think their systemic disease requires systemic therapy first, and, generally, we think first about giving a VEGF receptor TKI, sunitinib or pazopanib. How do you make the choice? How do you modify the therapy? And what has been the experience at MD Anderson?

Eric Jonasch, MD: We have 2 really good agents—sunitinib and pazopanib—that are both very viable options. From an efficacy perspective, if you look at the phase III data, there really isn’t a big difference. From a tolerability perspective, if you look at the COMPARZ study and you look at the PISCES study, what we see is there clearly are differences in the types of toxicities that the 2 drugs provide. For example, sunitinib probably has more fatigue, more taste changes, and more hand-foot syndrome. The pazopanib will cause hair changes and will cause transaminases. Nausea is something that’s under-reported, but definitely is a problem with that agent. So, there are differences between the 2. I think the equalizer for the 2 agents is how you give them—4 weeks on, 2 weeks off is the standard schedule for sunitinib, but more and more in the community, people are using alternating schedules that changes to a 2-week on schedule or other type of schedule changes. This type of insight into how to use these agents ends up making both drugs quite tolerable.

In terms of personal experience, from the late 2000s when pazopanib became available, it was our mainstay for a while. But as we become more and more comfortable with schedule changes in sunitinib, we’re using sunitinib more and more again. So, it’s interesting to see how our prescription patterns have changed. One of the other things is there’s further evolution of this. There’s an abstract at ASCO GU this year by Orenstein where what they did is a lead-in of 4 cycles of sunitinib. Those individuals who had at least a 10% decrease in tumor burden were then actually allowed to have a break with re-imaging, where re-initiation of sunitinib would occur if there was a 10% of regrowth. And this is a small study, but it’s just an example of strategies that are being used that can mitigate toxicity. The goal here is to keep people on a drug as long as possible with the least side effects. We have an abstract that’s also submitted at ASCO GU, and although our primary endpoint of grade 3 toxicities we were anticipating to reduce those to 15% or less, we still had 25%. But what we do see is that patients are staying on the drug longer, and we’re having progression-free survival and overall survivals that are better than historic data. We don’t know whether that’s because of the strategy, but I do believe that knowing how to use these drugs keeps people on longer, and you can’t have a response unless you’re actually being treated with the drug.

Robert A. Figlin, MD: Toni, I just wanted to push you a little bit. The Orenstein abstract that you also published in JCO suggesting of an intermittent approach, do you think there’s any evidence or could there be evidence that the development of resistance might be different if you give a drug and continue it versus intermittently giving it? You have a lot of experience in prostate cancer in a different disease where people might think that intermittent blockade is superior to continuous blockade. Can you give me your thoughts about that?

Toni K. Choueiri, MD: There are preclinical data that are supportive, but actually, the clinical data itself speaks against it. So, there is a trial that is run by Ian Davis from Australia that intermittently, based on the preclinical data, does sequence sunitinib and everolimus back and forth; mTOR and VEGF inhibitors. That did not show added toxicity. I would like to be careful in this. I think any VEGF tyrosine kinase inhibitor—if you use it enough, you’re familiar enough, you don’t follow the RECIST criteria well, you have a single-arm study—you can use them and get your progression-free survival to be more prolonged. I think we use the drugs very well. That’s what we do for a living. I think in the community, you cannot always expect the oncologist to have the clinic full of kidney cancer and to use sunitinib, pazopanib, cabozantinib, etc, as much. And perhaps this is one of the attractive things about using a fixed dose schedule of drug that is intravenous, like nivolumab, bevacizumab, and others. I would say that there has been experience with sunitinib. There is experience with axitinib in dose escalation, but the problem is, where do you draw the line? You can always keep the patient on as long as they’re not growing too quickly, they’re not experiencing significant side effects, and your PFS can be prolonged. It’s very important in this situation to have a control arm.

Transcript Edited for Clarity

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Transcript:

Robert A. Figlin, MD:
Toni, let me give you a few scenarios that I’d like for you to comment on because we see them in the office. A patient presents with a primary tumor in place with metastatic disease. So, what are your comments about cytoreductive nephrectomy in that setting? And then, once the decision is made on whether it’s been active surveillance or the patient is developing symptoms, you want to initiate therapy, what is your thought process for initiating therapy and the choice of agents?

Toni K. Choueiri, MD: The first question, going back, as a patient presents with kidney in place, is this patient eligible for a cytoreductive nephrectomy? Usually I try, if they’re eligible for cytoreductive nephrectomy, to get it out of the way initially. It does provide, in the appropriate clinical context, a survival benefit. I cannot say this is a level 1 evidence yet because there are trials ongoing. That may not actually answer the question, trials over 10 years slowly accruing that are ongoing, but at least, if you look retrospectively at retrospective studies as well as large national data set, there is a survival benefit from cytoreductive therapy in patients with limited disease burden and good performance status who can go to the operating room—so a lot of common sense. I try to get this out of the way, and it’s important because you will get additional information from a kidney that is removed that you may not be able to get from a biopsy, especially if a fine needle aspiration is done, that shows you general renal cell carcinoma. So, after that, and the patient is symptomatic, we need to start the treatment pretty quickly. I give usually around 2 weeks at least for the healing, sometimes more, especially if we have a clinical trial. And we start with a VEGF-targeted therapy normally.

Now our thought from almost 10 years ago about using temsirolimus in patients with poor-risk criteria, at least patients that present with metastatic disease with kidney in place have one criteria, so they’re at least intermediate. One more will make you poor at least, or 2 more per the Hudes criteria. But the problem with this is that this is an intravenous infusion weekly that is associated with a lower response rate, where in the clinical trial, the control arm was interferon. Retrospectively, several VEGF-targeted treatments showed efficacy in several subsets with poor-risk disease. So, if the patient is hospitalized, not doing well, you want to start the treatment and you want to start it fast—a quick prescription—then you start with temsirolimus. But, if you’re managing this patient as an outpatient, you have the time to start with an oral VEGF-targeted agent.

Robert A. Figlin, MD: Just to push you a little bit, Toni, there are patients where the primary tumor is there. Sometimes the extent of metastatic disease is greater than the volume of disease in the kidney. Sometimes the patient’s symptoms are not from the primary tumor, but from their metastatic disease. I just want to be clear, are there populations of patients where you think initiation of systemic therapy without cytoreductive therapy is an acceptable approach?

Toni K. Choueiri, MD: Absolutely, and those are the patients where you need to start systemic therapy and perhaps think about cytoreductive nephrectomy later. And sometimes, especially if you usually get single-agent, it’s rare to have an amazing response in the primary, but we don’t know. Perhaps with a novel combination, we don’t need any more cytoreductive nephrectomy. So, absolutely in these situations, systemic therapy is needed.

Robert A. Figlin, MD: Eric, we’re faced with the patient that Toni just described. The patients had their cytoreductive nephrectomy if appropriate. They’ve not had it if they think their systemic disease requires systemic therapy first, and, generally, we think first about giving a VEGF receptor TKI, sunitinib or pazopanib. How do you make the choice? How do you modify the therapy? And what has been the experience at MD Anderson?

Eric Jonasch, MD: We have 2 really good agents—sunitinib and pazopanib—that are both very viable options. From an efficacy perspective, if you look at the phase III data, there really isn’t a big difference. From a tolerability perspective, if you look at the COMPARZ study and you look at the PISCES study, what we see is there clearly are differences in the types of toxicities that the 2 drugs provide. For example, sunitinib probably has more fatigue, more taste changes, and more hand-foot syndrome. The pazopanib will cause hair changes and will cause transaminases. Nausea is something that’s under-reported, but definitely is a problem with that agent. So, there are differences between the 2. I think the equalizer for the 2 agents is how you give them—4 weeks on, 2 weeks off is the standard schedule for sunitinib, but more and more in the community, people are using alternating schedules that changes to a 2-week on schedule or other type of schedule changes. This type of insight into how to use these agents ends up making both drugs quite tolerable.

In terms of personal experience, from the late 2000s when pazopanib became available, it was our mainstay for a while. But as we become more and more comfortable with schedule changes in sunitinib, we’re using sunitinib more and more again. So, it’s interesting to see how our prescription patterns have changed. One of the other things is there’s further evolution of this. There’s an abstract at ASCO GU this year by Orenstein where what they did is a lead-in of 4 cycles of sunitinib. Those individuals who had at least a 10% decrease in tumor burden were then actually allowed to have a break with re-imaging, where re-initiation of sunitinib would occur if there was a 10% of regrowth. And this is a small study, but it’s just an example of strategies that are being used that can mitigate toxicity. The goal here is to keep people on a drug as long as possible with the least side effects. We have an abstract that’s also submitted at ASCO GU, and although our primary endpoint of grade 3 toxicities we were anticipating to reduce those to 15% or less, we still had 25%. But what we do see is that patients are staying on the drug longer, and we’re having progression-free survival and overall survivals that are better than historic data. We don’t know whether that’s because of the strategy, but I do believe that knowing how to use these drugs keeps people on longer, and you can’t have a response unless you’re actually being treated with the drug.

Robert A. Figlin, MD: Toni, I just wanted to push you a little bit. The Orenstein abstract that you also published in JCO suggesting of an intermittent approach, do you think there’s any evidence or could there be evidence that the development of resistance might be different if you give a drug and continue it versus intermittently giving it? You have a lot of experience in prostate cancer in a different disease where people might think that intermittent blockade is superior to continuous blockade. Can you give me your thoughts about that?

Toni K. Choueiri, MD: There are preclinical data that are supportive, but actually, the clinical data itself speaks against it. So, there is a trial that is run by Ian Davis from Australia that intermittently, based on the preclinical data, does sequence sunitinib and everolimus back and forth; mTOR and VEGF inhibitors. That did not show added toxicity. I would like to be careful in this. I think any VEGF tyrosine kinase inhibitor—if you use it enough, you’re familiar enough, you don’t follow the RECIST criteria well, you have a single-arm study—you can use them and get your progression-free survival to be more prolonged. I think we use the drugs very well. That’s what we do for a living. I think in the community, you cannot always expect the oncologist to have the clinic full of kidney cancer and to use sunitinib, pazopanib, cabozantinib, etc, as much. And perhaps this is one of the attractive things about using a fixed dose schedule of drug that is intravenous, like nivolumab, bevacizumab, and others. I would say that there has been experience with sunitinib. There is experience with axitinib in dose escalation, but the problem is, where do you draw the line? You can always keep the patient on as long as they’re not growing too quickly, they’re not experiencing significant side effects, and your PFS can be prolonged. It’s very important in this situation to have a control arm.

Transcript Edited for Clarity
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