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mRCC Patient Selection for Ipilimumab/Nivolumab

Panelists: Daniel George, MD, Duke Cancer Institute ; Robert J. Amato, MD, Memorial Hermann Cancer Center; Toni Choueiri, MD, Dana-Farber Cancer Institute; Richard W. Joseph, MD, Mayo Clinic; Walter Stadler, MD, University of Chicago
Published: Thursday, Jul 12, 2018



Transcript: 

Daniel George, MD: Well, let’s move on to the other new approval in the frontline metastatic RCC setting, and that is the nivolumab/ipilimumab combination based on the CheckMate-214 study. Walt, do you want to summarize that for us?

Walter Stadler, MD: This was a study that you all know was published in the New England Journal of Medicine, and this had a major impact on the field because it did show in a phase III trial that there was an improvement in survival over sunitinib. Interestingly, it was once again in the intermediate- and poor-risk population. In that article, buried in a paragraph on page 4 somewhere, are the data suggesting that in good-risk patients, sunitinib may actually be better. Certainly, ipilimumab plus nivolumab is not the better choice. I think that has been a little bit underrecognized, and perhaps we should talk a little bit about what that means in regard to selecting patients.

Daniel George, MD: We’re going to get to that topic in another session, so stay tuned; hold that thought. I want to follow up on the CheckMate-214 data because there was an important secondary endpoint, and that was response rate and, in particular, complete response rate. Now, Bob, I know as an oncologist in kidney cancer, you’ve been treating in this field for a long time, and getting patients to CR has always been a goal. How does that result with CheckMate-214, of a higher complete response rate, compare with sunitinib, and how does that factor into your decision in terms of selecting your starting therapy?

Robert J. Amato, MD: At the University of Texas, we try to individualize therapy as much as possible, and you know what I’m referring to. We’re trying to use immunotherapy markers for selection—PD-1, PD-L1—and there are other pathways we look at from an “-omics” perspective. Whether it’s proteomics or genomics, we have a multiomic program to look at selection. We’ve done the same thing with the frontline, second-line, and third-line tyrosine kinase inhibitors and mTOR inhibitors. We try to select the agent that’s suited for the individual. If that doesn’t work, then we fall back to the trials. Falling back to the trials, and a question I’m going to ask Walt in a minute for his opinion is about toxicity. With all these opportunities, these patients are going to their various oncologists within an academic setting in our Houston medical center to the community setting. They come with different opinions, and some of the opinions are, “You’re not a candidate for any therapy because you have comorbidities.” I think there is still a learning curve of how to select patients with comorbidities and disease presentation.

Daniel George, MD: That’s an excellent point. Both immunomarkers as enrichment strategies, and we can talk about the data in a minute on that. To the second point, and Walt, you can comment on this: How do we apply these CheckMate-214 data to the general public? Because a lot of those patients Bob is referring to with comorbidities would not be represented in a study population.

Walter Stadler, MD: Correct, and I think that the community oncologists are becoming more familiar with the immunotherapy toxicities. It is now not only in melanoma and renal cancer but also in lung cancer. The practitioners that are out there are beginning to become familiar with this. That being said, I think we have to recognize that this combination immunotherapy leads to very severe toxicities in 5% to 10% of patients. If I recall correctly, in the New England Journal of Medicine, in our article, it is like 3% death rate, and this is significant. I think that especially in the context of a broader community where sometimes these toxicities show up on a weekend, perhaps being evaluated by urgent care physicians or hospitalists without consultation with people who are experts, bad things happen, and I think we have to recognize that, and we also have to recognize that patients with preexisting autoimmune diseases are going to be more susceptible to these kinds of events. Then things like cabozantinib may come into play, but there we have to consider things like hypertension, managing hypertension with these VEGFR TKIs, managing the fatigue, managing the hypothyroidism. All of these are things that oncologists can learn. My statement has always been that a well-trained oncologist knows how to give cisplatin, which is probably the most toxic drug that I know. Oncologists will learn how to do this, but there is still a learning curve, and with the introduction of all these agents at the same time, the learning curve does mean that unfortunately sometimes patients will get hurt.

Robert J. Amato, MD: May I ask a question?

Walter Stadler, MD: Yes.

Robert J. Amato, MD: You’re an expert in kidney cancer, and you’ve seen, as much as every panel member, these mixed responses, independent of whether we’re using cytokines, TKs, mTORs. But now I have these checkpoint inhibitors, and we see this pseudoprogression that we’re trying to understand, and it’s a challenge for us. Is this true progression? Is this inflammatory change? Is it going to improve the longer they’re on it? All the questions we discuss among ourselves and our colleagues at our respective universities. How do we teach the community oncologist who doesn’t see renal cell cancer every day, and they get this report from the radiologist, or they look at it themselves with the radiologist and they see pseudoprogression, and we try to convince them, “Stay on. It’s OK. Repeat the scan in 6 or 8 more weeks to see what may be taking place”?

Walter Stadler, MD: From my perspective, a little common sense goes a long way. The vast majority of pseudoprogression is real progression, but this is where having the patient in front of you, and the CT scan in front of you at the same time is helpful, right? With our modern electronic medical records, where we can look at the CT and the patient at the same time, it really helps us. So, if there’s a little bit of a progression because the lymph node went from 1.5 to 1.8 cm, and the radiologist says that’s progression and the patient says, “I’m feeling better,” let’s use some common sense. If the pseudoprogression is that your 4-cm lung mass is now 8 cm, and the patient is feeling bad, that’s not pseudoprogression; that’s real progression. I think that goes a long way.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: Well, let’s move on to the other new approval in the frontline metastatic RCC setting, and that is the nivolumab/ipilimumab combination based on the CheckMate-214 study. Walt, do you want to summarize that for us?

Walter Stadler, MD: This was a study that you all know was published in the New England Journal of Medicine, and this had a major impact on the field because it did show in a phase III trial that there was an improvement in survival over sunitinib. Interestingly, it was once again in the intermediate- and poor-risk population. In that article, buried in a paragraph on page 4 somewhere, are the data suggesting that in good-risk patients, sunitinib may actually be better. Certainly, ipilimumab plus nivolumab is not the better choice. I think that has been a little bit underrecognized, and perhaps we should talk a little bit about what that means in regard to selecting patients.

Daniel George, MD: We’re going to get to that topic in another session, so stay tuned; hold that thought. I want to follow up on the CheckMate-214 data because there was an important secondary endpoint, and that was response rate and, in particular, complete response rate. Now, Bob, I know as an oncologist in kidney cancer, you’ve been treating in this field for a long time, and getting patients to CR has always been a goal. How does that result with CheckMate-214, of a higher complete response rate, compare with sunitinib, and how does that factor into your decision in terms of selecting your starting therapy?

Robert J. Amato, MD: At the University of Texas, we try to individualize therapy as much as possible, and you know what I’m referring to. We’re trying to use immunotherapy markers for selection—PD-1, PD-L1—and there are other pathways we look at from an “-omics” perspective. Whether it’s proteomics or genomics, we have a multiomic program to look at selection. We’ve done the same thing with the frontline, second-line, and third-line tyrosine kinase inhibitors and mTOR inhibitors. We try to select the agent that’s suited for the individual. If that doesn’t work, then we fall back to the trials. Falling back to the trials, and a question I’m going to ask Walt in a minute for his opinion is about toxicity. With all these opportunities, these patients are going to their various oncologists within an academic setting in our Houston medical center to the community setting. They come with different opinions, and some of the opinions are, “You’re not a candidate for any therapy because you have comorbidities.” I think there is still a learning curve of how to select patients with comorbidities and disease presentation.

Daniel George, MD: That’s an excellent point. Both immunomarkers as enrichment strategies, and we can talk about the data in a minute on that. To the second point, and Walt, you can comment on this: How do we apply these CheckMate-214 data to the general public? Because a lot of those patients Bob is referring to with comorbidities would not be represented in a study population.

Walter Stadler, MD: Correct, and I think that the community oncologists are becoming more familiar with the immunotherapy toxicities. It is now not only in melanoma and renal cancer but also in lung cancer. The practitioners that are out there are beginning to become familiar with this. That being said, I think we have to recognize that this combination immunotherapy leads to very severe toxicities in 5% to 10% of patients. If I recall correctly, in the New England Journal of Medicine, in our article, it is like 3% death rate, and this is significant. I think that especially in the context of a broader community where sometimes these toxicities show up on a weekend, perhaps being evaluated by urgent care physicians or hospitalists without consultation with people who are experts, bad things happen, and I think we have to recognize that, and we also have to recognize that patients with preexisting autoimmune diseases are going to be more susceptible to these kinds of events. Then things like cabozantinib may come into play, but there we have to consider things like hypertension, managing hypertension with these VEGFR TKIs, managing the fatigue, managing the hypothyroidism. All of these are things that oncologists can learn. My statement has always been that a well-trained oncologist knows how to give cisplatin, which is probably the most toxic drug that I know. Oncologists will learn how to do this, but there is still a learning curve, and with the introduction of all these agents at the same time, the learning curve does mean that unfortunately sometimes patients will get hurt.

Robert J. Amato, MD: May I ask a question?

Walter Stadler, MD: Yes.

Robert J. Amato, MD: You’re an expert in kidney cancer, and you’ve seen, as much as every panel member, these mixed responses, independent of whether we’re using cytokines, TKs, mTORs. But now I have these checkpoint inhibitors, and we see this pseudoprogression that we’re trying to understand, and it’s a challenge for us. Is this true progression? Is this inflammatory change? Is it going to improve the longer they’re on it? All the questions we discuss among ourselves and our colleagues at our respective universities. How do we teach the community oncologist who doesn’t see renal cell cancer every day, and they get this report from the radiologist, or they look at it themselves with the radiologist and they see pseudoprogression, and we try to convince them, “Stay on. It’s OK. Repeat the scan in 6 or 8 more weeks to see what may be taking place”?

Walter Stadler, MD: From my perspective, a little common sense goes a long way. The vast majority of pseudoprogression is real progression, but this is where having the patient in front of you, and the CT scan in front of you at the same time is helpful, right? With our modern electronic medical records, where we can look at the CT and the patient at the same time, it really helps us. So, if there’s a little bit of a progression because the lymph node went from 1.5 to 1.8 cm, and the radiologist says that’s progression and the patient says, “I’m feeling better,” let’s use some common sense. If the pseudoprogression is that your 4-cm lung mass is now 8 cm, and the patient is feeling bad, that’s not pseudoprogression; that’s real progression. I think that goes a long way.

Transcript Edited for Clarity 
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