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Treatment Options in Renal Cell Carcinoma

Panelists:Robert A. Figlin, MD, Cedars-Sinai Medical Center; Sandy Srinivas, MD, Stanford University Medical Center; Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Feb 04, 2016


Transcript:

Robert A. Figlin, MD:
Hello, and thank you for joining this OncLive TV Peer Exchange. There has been considerable progress in the treatment of advanced renal-cell carcinoma over the last decade, with several VEGF-targeted agents and two mTOR inhibitors approved by the FDA. Now, most recently, we have added nivolumab to our therapeutic arsenal. As we learn how to optimally use and sequence these agents in patients, we expect the approval of additional new targeted therapies as well as other checkpoint inhibitors.

With all of this new opportunity, there is also added complexity as to how to choose the right course of treatment for the individual patients. In this OncLive Peer Exchange, my colleagues and I will discuss the latest information on how to use the agents we have available today, and where the newest agents will fit into the treatment paradigm.

I’m Dr. Robert Figlin, Steven Spielberg Family Chair in Hematology/Oncology; Professor of Medicine and Biomedical Sciences; Director for the Division of Hematology/Oncology; and Deputy Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center. Joining me today are: Dr. Sandy Srinivas, an Associate Professor of Medicine and Oncology at Stanford University Medical Center; Dr. Nizar Tannir, Professor and Deputy Chairman for the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center; and Dr. Martin Voss, a Medical Oncologist at Memorial Sloan Kettering Cancer Center. Thank you to each of you for joining us today. Now, let’s get started.

So let’s start, Sandy, by talking about what is commonly the challenge for most doctors in the community. They have a patient who’s presenting to them. They have to decide when to start therapy. It’s a kidney cancer patient, already metastatic, and they have to decide when to start therapy and what the goals of therapy are going to be. What would you answer to that?

Sandy Srinivas, MD: Over the last decade, I’ve come to realize that you don’t need to start therapy on patients right away. So I wait to make sure that there is growing disease; so, it’s not uncommon to see patients with small lung mets which are not biopsiable. So, I’m very comfortable about monitoring and waiting till there is growing disease, but, on the other hand, there are patients who are symptomatic who have bulky disease. And I think those patients I would feel very comfortable offering them therapy right away. And then there are patients who are young and clearly there is an anxiety factor, as well, which we need to take into consideration. So I think all of this needs to be considered before offering patients therapy.

Robert A. Figlin, MD: And then, what do you say to them about what your goals are with either a targeted therapy, an mTOR inhibitor or therapeutic options that are out there?

Sandy Srinivas, MD: I always lay out in my mind what are the goals, so I think about cure as our number one goal. And I think that’s important to have in mind, and with the current treatment and clearly, this may change with more immunotherapeutics becoming available. But I think I offer high-dose IL-2 to patients with an intent of cure. Then, if cure is not an option, I also look for those patients who may have oligometastatic disease where you may offer them some systemic therapy and combine it with some local therapy with an intent for cure or maybe even long disease pre-interval.

So, if cure is not an option, we now know with all of these agents that we have had for a decade that we are clearly helping patients live longer. So I think prolongation of survival and delaying progression of disease is a very important objective. And finally, I think quality of life becomes a big issue, especially as many of these patients live with this disease during their entire lifetime. All of these should be considerations in deciding which drug you are going to pick.

Robert A. Figlin, MD: So, Martin, it would be nice if we could pick out the winners from the patients whom we treat, those who are going to benefit and those who aren’t. Does the literature help us understand if there are predictive factors or how to choose people who are more likely to benefit from the agents that are available to us?

Martin H. Voss, MD: So, there are no validated established predictive factors that can, with certainty, predict that one agent is superior over the other. And, of course, that’s been heavily investigated by many. We have a whole host of smaller and larger studies that have looked into predictive factors from the tissue, and from the serum that are meant to predict whether or not patients respond to some of the standard approved agents. And we certainly have a signal for some of them.

There’s recent data from our own institution that was presented at ASCO last year looking into a randomized trial that compared an mTOR inhibitor, everolimus, to a VEGF TKI, sunitinib, and looked at a host of different candidate genes, and mutation status there, to see if we could find for sunitinib therapy and for everolimus therapy, whether or not driver mutations in the tumor tissue might predict for superior outcome with one over the other. And, bottom line was not helpful in selecting one of the two agents, but, within each of the agents, there are some mutations that can help to understand if a patient has a higher or lower likelihood of benefitting from the drug.

So, an example for that being a PBRM1 mutation status and mTOR inhibitor therapy, it appears that patients with PBRM1 mutations are more likely to benefit than the patients that are wild-type. And for sunitinib therapy, there seem to be a signal that KDM5C mutation seems to correlate with superior outcome over KDM5C wild-type patients. Now, none of that helps you decide which agent to use because patients still can benefit from either of the two. So all of this is sort of still in the early phases of investigation. In standard practice, in my own practice, there are no tissue-based predictive factors that help us decide between drugs.

So, the question then becomes how you choose which agent to use in the first-line setting with the FDA approved options we have; VEGF and tyrosine kinase inhibitors (TKIs), sunitinib, pazopanib, and mTOR inhibitor, temsirolimus, or just mentioned high-dose IL-2. More than anything, performance status and comorbidities help make that decision. A patient who is very compromised at baseline is unlikely to be a good candidate for an aggressive treatment like high-dose IL-2. A patient with significant cardiac disease is not a great candidate for VEGF TKI, and a patient with poorly controlled diabetes might not be best suited with an mTOR inhibitor. So it can help steer you in a certain direction.

Robert A. Figlin, MD: So it sounds as though comorbidities play a significant role in the choice of upfront therapies as much as whether it’s good, intermediate, or poor prognosis RCC patients. Would you agree with that?

Martin H. Voss, MD: I would agree with that. So the MSKCC risk status that you’re referring to for many of us, certainly in my practice, is not something that helps guide our decision making in day-to-day practice, but is more a tool for clinical trial design, a stratification for patients on trials.

Robert A. Figlin, MD: Sandy, your thoughts?

Sandy Srinivas, MD: I was just going to say that I kind of think about it as patient characteristics, drug characteristics, and disease characteristics and think about symptomatic, asymptomatic, performance status as patient characteristics. We are not there yet, but I think already in practice you are thinking about what’s appropriate for clear-cell and non-clear-cell and finally some of the comorbidities that they have. Patients coming in with profound, who are already on five antihypertensives coming in, you might be a little hesitant in thinking about what’s best for them or a patient with bad diabetes, you may pick one drug or the other.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Hello, and thank you for joining this OncLive TV Peer Exchange. There has been considerable progress in the treatment of advanced renal-cell carcinoma over the last decade, with several VEGF-targeted agents and two mTOR inhibitors approved by the FDA. Now, most recently, we have added nivolumab to our therapeutic arsenal. As we learn how to optimally use and sequence these agents in patients, we expect the approval of additional new targeted therapies as well as other checkpoint inhibitors.

With all of this new opportunity, there is also added complexity as to how to choose the right course of treatment for the individual patients. In this OncLive Peer Exchange, my colleagues and I will discuss the latest information on how to use the agents we have available today, and where the newest agents will fit into the treatment paradigm.

I’m Dr. Robert Figlin, Steven Spielberg Family Chair in Hematology/Oncology; Professor of Medicine and Biomedical Sciences; Director for the Division of Hematology/Oncology; and Deputy Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center. Joining me today are: Dr. Sandy Srinivas, an Associate Professor of Medicine and Oncology at Stanford University Medical Center; Dr. Nizar Tannir, Professor and Deputy Chairman for the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center; and Dr. Martin Voss, a Medical Oncologist at Memorial Sloan Kettering Cancer Center. Thank you to each of you for joining us today. Now, let’s get started.

So let’s start, Sandy, by talking about what is commonly the challenge for most doctors in the community. They have a patient who’s presenting to them. They have to decide when to start therapy. It’s a kidney cancer patient, already metastatic, and they have to decide when to start therapy and what the goals of therapy are going to be. What would you answer to that?

Sandy Srinivas, MD: Over the last decade, I’ve come to realize that you don’t need to start therapy on patients right away. So I wait to make sure that there is growing disease; so, it’s not uncommon to see patients with small lung mets which are not biopsiable. So, I’m very comfortable about monitoring and waiting till there is growing disease, but, on the other hand, there are patients who are symptomatic who have bulky disease. And I think those patients I would feel very comfortable offering them therapy right away. And then there are patients who are young and clearly there is an anxiety factor, as well, which we need to take into consideration. So I think all of this needs to be considered before offering patients therapy.

Robert A. Figlin, MD: And then, what do you say to them about what your goals are with either a targeted therapy, an mTOR inhibitor or therapeutic options that are out there?

Sandy Srinivas, MD: I always lay out in my mind what are the goals, so I think about cure as our number one goal. And I think that’s important to have in mind, and with the current treatment and clearly, this may change with more immunotherapeutics becoming available. But I think I offer high-dose IL-2 to patients with an intent of cure. Then, if cure is not an option, I also look for those patients who may have oligometastatic disease where you may offer them some systemic therapy and combine it with some local therapy with an intent for cure or maybe even long disease pre-interval.

So, if cure is not an option, we now know with all of these agents that we have had for a decade that we are clearly helping patients live longer. So I think prolongation of survival and delaying progression of disease is a very important objective. And finally, I think quality of life becomes a big issue, especially as many of these patients live with this disease during their entire lifetime. All of these should be considerations in deciding which drug you are going to pick.

Robert A. Figlin, MD: So, Martin, it would be nice if we could pick out the winners from the patients whom we treat, those who are going to benefit and those who aren’t. Does the literature help us understand if there are predictive factors or how to choose people who are more likely to benefit from the agents that are available to us?

Martin H. Voss, MD: So, there are no validated established predictive factors that can, with certainty, predict that one agent is superior over the other. And, of course, that’s been heavily investigated by many. We have a whole host of smaller and larger studies that have looked into predictive factors from the tissue, and from the serum that are meant to predict whether or not patients respond to some of the standard approved agents. And we certainly have a signal for some of them.

There’s recent data from our own institution that was presented at ASCO last year looking into a randomized trial that compared an mTOR inhibitor, everolimus, to a VEGF TKI, sunitinib, and looked at a host of different candidate genes, and mutation status there, to see if we could find for sunitinib therapy and for everolimus therapy, whether or not driver mutations in the tumor tissue might predict for superior outcome with one over the other. And, bottom line was not helpful in selecting one of the two agents, but, within each of the agents, there are some mutations that can help to understand if a patient has a higher or lower likelihood of benefitting from the drug.

So, an example for that being a PBRM1 mutation status and mTOR inhibitor therapy, it appears that patients with PBRM1 mutations are more likely to benefit than the patients that are wild-type. And for sunitinib therapy, there seem to be a signal that KDM5C mutation seems to correlate with superior outcome over KDM5C wild-type patients. Now, none of that helps you decide which agent to use because patients still can benefit from either of the two. So all of this is sort of still in the early phases of investigation. In standard practice, in my own practice, there are no tissue-based predictive factors that help us decide between drugs.

So, the question then becomes how you choose which agent to use in the first-line setting with the FDA approved options we have; VEGF and tyrosine kinase inhibitors (TKIs), sunitinib, pazopanib, and mTOR inhibitor, temsirolimus, or just mentioned high-dose IL-2. More than anything, performance status and comorbidities help make that decision. A patient who is very compromised at baseline is unlikely to be a good candidate for an aggressive treatment like high-dose IL-2. A patient with significant cardiac disease is not a great candidate for VEGF TKI, and a patient with poorly controlled diabetes might not be best suited with an mTOR inhibitor. So it can help steer you in a certain direction.

Robert A. Figlin, MD: So it sounds as though comorbidities play a significant role in the choice of upfront therapies as much as whether it’s good, intermediate, or poor prognosis RCC patients. Would you agree with that?

Martin H. Voss, MD: I would agree with that. So the MSKCC risk status that you’re referring to for many of us, certainly in my practice, is not something that helps guide our decision making in day-to-day practice, but is more a tool for clinical trial design, a stratification for patients on trials.

Robert A. Figlin, MD: Sandy, your thoughts?

Sandy Srinivas, MD: I was just going to say that I kind of think about it as patient characteristics, drug characteristics, and disease characteristics and think about symptomatic, asymptomatic, performance status as patient characteristics. We are not there yet, but I think already in practice you are thinking about what’s appropriate for clear-cell and non-clear-cell and finally some of the comorbidities that they have. Patients coming in with profound, who are already on five antihypertensives coming in, you might be a little hesitant in thinking about what’s best for them or a patient with bad diabetes, you may pick one drug or the other.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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