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Selecting Immunotherapy versus VEGF TKI for mRCC

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: Monday, Jul 30, 2018



Transcript: 

Daniel George, MD: I want to step back and take the prognostic score now by group. So, if we look at the intermediate-to-poor-risk group as a collective—and I know those aren’t the same, but we recognize on the spectrum—they are that half of the spectrum which, now we have some studies that have specifically focused on those populations, have given us some new data and perspectives on this. How are you choosing, for your intermediate- and poor-risk patients, which therapy to start with?

Richard W. Joseph, MD: This is one of the most critical questions that I have in the clinic right now when presented with an intermediate/poor. We have at least 1 phase III study with ipilimumab plus nivolumab showing superiority in both overall response and overall survival, and pretty close to PFS; I guess it was statistically not there. Then you have the phase II CABOSUN trial where you have cabozantinib beating out sunitinib but neither of them have been compared head to head. So, how do you go with an immune therapy versus a TKI? Well, obviously, the easy things are if they have immune problems; that makes it easy. What if they don’t? Well, some of the things that I think about, that I don’t necessarily know for a fact are true, but at least from experience, is perhaps the bone-predominant patients might be better fit for a TKI rather than immunotherapy. I think PD-L1 status might be able to help you. Especially the patients who are PD-L1 positive seem to have even more improved outcomes over the TKIs.

There is some question about maybe even in CABOSUN—this is not something we do routinely—but maybe a biomarker for them; maybe MET expression could be a hypothesis-generating way of trying to select patients that might go that way. I don’t really have a great answer for the question other than the obvious ones like, history of autoimmune disorders.

Daniel George, MD: Toni, what about you? How are you choosing? There are tools available, then there are tools that are not available. There are clinical trials we can ask. But at the end of the day, you have to do clinic next week, and you see a newly diagnosed intermediate-risk patient. What are you going to start them on?

Toni Choueiri, MD: Well, bearing some clinical trial was always my first choice. Where’s the overall survival benefit from CheckMate-214? You have to see what are the reasons for not giving nivolumab plus ipilimumab. You’d be surprised. We still—despite the great electronic medical record system—have to take good history. You’d be surprised how many patients have autoimmune disease, whether in remission or not, and are on methotrexate, etc; so that’s one. Second, predominant bone disease. There are data evolving with cabozantinib. Third, something we don’t talk in trial is that, as you know, one-third of our patients are not eligible for trial. We looked at that from the IMVC database, and some of those patients, what can you do if they have organ dysfunction? Fourth, and most important, is when someone has a very, very aggressive disease and you can’t get nivolumab plus ipilimumab immediately.

The rate of PD (progressive disease) as best response with cabozantinib, both on CABOSUN and on METEOR, the second line is really low, while with immunotherapy, it could be high. Perhaps this is something that can slow down the disease—not different from chemotherapy—versus checkpoint inhibitors in bladder cancer, for example. That’s another reason to consider it, and let’s not forget: Walt was saying that we do have today, for the community oncologist, more experience with VEGF TKI therapy and management, rather than checkpoint inhibitor or double checkpoint inhibitor. These all factor in, that it’s not an easy thing, and it’s going to get more difficult when the combination VEGF immunotherapy come into play.

Daniel George, MD: Absolutely. We’re going to get to that in a minute.

Walter Stadler, MD: I think that’s fascinating, Toni, and one thing I may want to come back to a little bit from what Richard said in regard to these trials. They bring up more questions sometimes than they answer. I have been impressed not only with this intermediate-/poor-risk level 3 data, but corroboration in the clinic where sometimes some of our worst patients actually do pretty well with this immunotherapy, as opposed to the good-risk patients who putter along. My clinical experience mirrors what the level 1 data show us, and one of my question is, why? What is the biology behind that? Poor risk basically says the patient doesn’t look so good, isn’t doing so well, and here are some labs. But that doesn’t tell me about why this is happening. I think it raises some very interesting hypotheses, which will hopefully get us to a more refined selection of our therapies.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: I want to step back and take the prognostic score now by group. So, if we look at the intermediate-to-poor-risk group as a collective—and I know those aren’t the same, but we recognize on the spectrum—they are that half of the spectrum which, now we have some studies that have specifically focused on those populations, have given us some new data and perspectives on this. How are you choosing, for your intermediate- and poor-risk patients, which therapy to start with?

Richard W. Joseph, MD: This is one of the most critical questions that I have in the clinic right now when presented with an intermediate/poor. We have at least 1 phase III study with ipilimumab plus nivolumab showing superiority in both overall response and overall survival, and pretty close to PFS; I guess it was statistically not there. Then you have the phase II CABOSUN trial where you have cabozantinib beating out sunitinib but neither of them have been compared head to head. So, how do you go with an immune therapy versus a TKI? Well, obviously, the easy things are if they have immune problems; that makes it easy. What if they don’t? Well, some of the things that I think about, that I don’t necessarily know for a fact are true, but at least from experience, is perhaps the bone-predominant patients might be better fit for a TKI rather than immunotherapy. I think PD-L1 status might be able to help you. Especially the patients who are PD-L1 positive seem to have even more improved outcomes over the TKIs.

There is some question about maybe even in CABOSUN—this is not something we do routinely—but maybe a biomarker for them; maybe MET expression could be a hypothesis-generating way of trying to select patients that might go that way. I don’t really have a great answer for the question other than the obvious ones like, history of autoimmune disorders.

Daniel George, MD: Toni, what about you? How are you choosing? There are tools available, then there are tools that are not available. There are clinical trials we can ask. But at the end of the day, you have to do clinic next week, and you see a newly diagnosed intermediate-risk patient. What are you going to start them on?

Toni Choueiri, MD: Well, bearing some clinical trial was always my first choice. Where’s the overall survival benefit from CheckMate-214? You have to see what are the reasons for not giving nivolumab plus ipilimumab. You’d be surprised. We still—despite the great electronic medical record system—have to take good history. You’d be surprised how many patients have autoimmune disease, whether in remission or not, and are on methotrexate, etc; so that’s one. Second, predominant bone disease. There are data evolving with cabozantinib. Third, something we don’t talk in trial is that, as you know, one-third of our patients are not eligible for trial. We looked at that from the IMVC database, and some of those patients, what can you do if they have organ dysfunction? Fourth, and most important, is when someone has a very, very aggressive disease and you can’t get nivolumab plus ipilimumab immediately.

The rate of PD (progressive disease) as best response with cabozantinib, both on CABOSUN and on METEOR, the second line is really low, while with immunotherapy, it could be high. Perhaps this is something that can slow down the disease—not different from chemotherapy—versus checkpoint inhibitors in bladder cancer, for example. That’s another reason to consider it, and let’s not forget: Walt was saying that we do have today, for the community oncologist, more experience with VEGF TKI therapy and management, rather than checkpoint inhibitor or double checkpoint inhibitor. These all factor in, that it’s not an easy thing, and it’s going to get more difficult when the combination VEGF immunotherapy come into play.

Daniel George, MD: Absolutely. We’re going to get to that in a minute.

Walter Stadler, MD: I think that’s fascinating, Toni, and one thing I may want to come back to a little bit from what Richard said in regard to these trials. They bring up more questions sometimes than they answer. I have been impressed not only with this intermediate-/poor-risk level 3 data, but corroboration in the clinic where sometimes some of our worst patients actually do pretty well with this immunotherapy, as opposed to the good-risk patients who putter along. My clinical experience mirrors what the level 1 data show us, and one of my question is, why? What is the biology behind that? Poor risk basically says the patient doesn’t look so good, isn’t doing so well, and here are some labs. But that doesn’t tell me about why this is happening. I think it raises some very interesting hypotheses, which will hopefully get us to a more refined selection of our therapies.

Transcript Edited for Clarity 
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