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Sequencing Renal Cell Carcinoma Therapies

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: Wednesday, Feb 24, 2016


Transcript:

Robert A. Figlin, MD:
Martin, again to put you on the spot: we’re faced with a dilemma of riches. We have nine drugs that are now commercially available in kidney cancer. We’ve described very nicely, through your comments, what we do in the frontline setting. There are yet no data in the front-line setting about immune-based therapy outside of IL-2, and then we have many patients that progress to require second-line treatment. And we have multiple agents approved in the second-line. Axitinib is approved in the second-line, a VEGF receptor-targeted agent. Nivolumab has now been shown to be superior to everolimus, and there may be more down the road. So the question is: how are you deciding in your practice what the proper sequence should be and is it based upon data or is it based upon an emotional belief that treatment A is better than treatment B? How are you discussing that with your patient?

Martin H. Voss, MD: It’s a mix of different things. I think data should always be a part of it, and the best example of that is now the CheckMate 025 study and also the METEOR trial that we haven’t talked about yet, but also trials in the phase III setting that are comparing some of these agents available to us now and showing some to be superior over others. In a patient who is doing well and where comorbidities don’t direct us in one direction versus the other, I would choose the agent with superior overall survival and certainly over the medication that fell short on a trial. But it’s not always that easy. And the things that must be integrated also into that decision process outside of clinical trials is, for one, the existence of comorbidities, and we’ve mentioned this now several times.

There are patients who are not good candidates for checkpoint inhibitors, for instance, because they’re already on immunosuppressants for an underlying autoimmune disease. So a patient who has active rheumatoid arthritis, you’re going to be hard-pressed to put on a checkpoint inhibitor because you may make the underlying autoimmune disease worse. We actually don’t know that that is the case because those patients were included from clinical trials with checkpoint inhibitors, and there are actually some early data, again from melanoma, to show that it may be safe for some of those patients. But certainly it’s an important consideration given that we have so many other agents available. And just because medication is new and has some promising data doesn’t mean that it must be the one that we choose.

And then, secondly: patients participate in these decisions, and I have patients who are highly enthusiastic about immunotherapy and it’s all that they want to hear about. But there are also patients who hate coming to clinic every two weeks for an infusion. Or some patients have a phobia of needles; they don’t want to get an IV drug. And it’s something that we can’t ignore just because there is evidence that suggests that there are superior data on several endpoints. Because for the majority of these patients, these agents are not going to be curative and they are going to be subjected to the other agent at a later point. So choosing the right sequence, I think, integrates the data that we have: the patient preference, comorbidities, and also how they fared with prior agents. Someone who’s been on a tyrosine kinase inhibitor for extended periods of time and is worn out from all the class-specific toxicities they’ve had may be very relieved to switch to a different class of agents and catch a break from all the hypertension and hand-foot syndrome that they’ve had.

Robert A. Figlin, MD: Nizar, not that it’s easy to choose a second-line treatment, but now we’re all going to be faced with what do we do if we have chosen a checkpoint inhibitor in the second-line because there are really a paucity of data of what to do then. We don’t know, nor do we have data to talk about VEGF-receptor TKI inhibition post-checkpoint inhibition. There’s still mTOR inhibition. How are you navigating through this complex area, especially when you see somebody that has clearly clinically progressed on a checkpoint inhibitor but is still well enough to receive a third-line agent?

Nizar M. Tannir, MD, FACP: Sure. I think, as we have said, especially when it comes to clear-cell RCC, we have more data with targeted agents, especially the VEGFR TKIs. This is predominantly a VEGF-driven disease. And even after a first-line therapy with a VEGFR TKI and let’s say an immune checkpoint such as nivolumab, the disease remains VEGF-driven. Therefore, I think it makes sense to use another VEGF-directed therapy post-nivolumab. Now, obviously, axitinib is FDA-approved and is on the market, and we use that. And I have had patients respond to axitinib after first-line therapy, as well as immune checkpoint inhibitors.

I think we will be discussing METEOR and cabozantinib, which is not FDA-approved yet. But certainly, I think that is a drug that has a unique mechanism of action, and it’s a little bit different than the VEGF-directed therapies that we have on the market because it also targets c-MET and AXL. These are two pathways that are relevant in progressive RCC. Therefore, I think it makes sense to use cabozantinib in this setting. I think mTOR inhibitors have fallen, especially everolimus, into the salvage setting. It’s been falling from its second- or third-line space because the two phase III trials. With nivolumab, there is CheckMate 025 that we discussed and then there is the METEOR trial studying cabozantinib. Both of these, METEOR and CheckMate 025, used everolimus for a comparator and it was found to be inferior.

Having said that, I think there’s still a role for mTOR inhibitors. If the patient still has a good performance status, obviously, if there’s a clinical trial, I think that would be preferred to enroll the patient. But outside of the context of a clinical trial, if they have not received an mTOR inhibitor, I think it behooves us to try mTOR inhibitors because the patient may have a genomic alteration in their tumor that makes it sensitive to mTOR blockade. And we discussed earlier about the mTOR gene pathway: TSC1, TSC2, and PTEN, and PI3 kinase, etc; those genes may be in 5%, 10% of the tumors. But I think it is still important to not overlook completely the mTOR inhibitors in the salvage setting.
                                                                                                                                                                                                                                                                                                                 Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Martin, again to put you on the spot: we’re faced with a dilemma of riches. We have nine drugs that are now commercially available in kidney cancer. We’ve described very nicely, through your comments, what we do in the frontline setting. There are yet no data in the front-line setting about immune-based therapy outside of IL-2, and then we have many patients that progress to require second-line treatment. And we have multiple agents approved in the second-line. Axitinib is approved in the second-line, a VEGF receptor-targeted agent. Nivolumab has now been shown to be superior to everolimus, and there may be more down the road. So the question is: how are you deciding in your practice what the proper sequence should be and is it based upon data or is it based upon an emotional belief that treatment A is better than treatment B? How are you discussing that with your patient?

Martin H. Voss, MD: It’s a mix of different things. I think data should always be a part of it, and the best example of that is now the CheckMate 025 study and also the METEOR trial that we haven’t talked about yet, but also trials in the phase III setting that are comparing some of these agents available to us now and showing some to be superior over others. In a patient who is doing well and where comorbidities don’t direct us in one direction versus the other, I would choose the agent with superior overall survival and certainly over the medication that fell short on a trial. But it’s not always that easy. And the things that must be integrated also into that decision process outside of clinical trials is, for one, the existence of comorbidities, and we’ve mentioned this now several times.

There are patients who are not good candidates for checkpoint inhibitors, for instance, because they’re already on immunosuppressants for an underlying autoimmune disease. So a patient who has active rheumatoid arthritis, you’re going to be hard-pressed to put on a checkpoint inhibitor because you may make the underlying autoimmune disease worse. We actually don’t know that that is the case because those patients were included from clinical trials with checkpoint inhibitors, and there are actually some early data, again from melanoma, to show that it may be safe for some of those patients. But certainly it’s an important consideration given that we have so many other agents available. And just because medication is new and has some promising data doesn’t mean that it must be the one that we choose.

And then, secondly: patients participate in these decisions, and I have patients who are highly enthusiastic about immunotherapy and it’s all that they want to hear about. But there are also patients who hate coming to clinic every two weeks for an infusion. Or some patients have a phobia of needles; they don’t want to get an IV drug. And it’s something that we can’t ignore just because there is evidence that suggests that there are superior data on several endpoints. Because for the majority of these patients, these agents are not going to be curative and they are going to be subjected to the other agent at a later point. So choosing the right sequence, I think, integrates the data that we have: the patient preference, comorbidities, and also how they fared with prior agents. Someone who’s been on a tyrosine kinase inhibitor for extended periods of time and is worn out from all the class-specific toxicities they’ve had may be very relieved to switch to a different class of agents and catch a break from all the hypertension and hand-foot syndrome that they’ve had.

Robert A. Figlin, MD: Nizar, not that it’s easy to choose a second-line treatment, but now we’re all going to be faced with what do we do if we have chosen a checkpoint inhibitor in the second-line because there are really a paucity of data of what to do then. We don’t know, nor do we have data to talk about VEGF-receptor TKI inhibition post-checkpoint inhibition. There’s still mTOR inhibition. How are you navigating through this complex area, especially when you see somebody that has clearly clinically progressed on a checkpoint inhibitor but is still well enough to receive a third-line agent?

Nizar M. Tannir, MD, FACP: Sure. I think, as we have said, especially when it comes to clear-cell RCC, we have more data with targeted agents, especially the VEGFR TKIs. This is predominantly a VEGF-driven disease. And even after a first-line therapy with a VEGFR TKI and let’s say an immune checkpoint such as nivolumab, the disease remains VEGF-driven. Therefore, I think it makes sense to use another VEGF-directed therapy post-nivolumab. Now, obviously, axitinib is FDA-approved and is on the market, and we use that. And I have had patients respond to axitinib after first-line therapy, as well as immune checkpoint inhibitors.

I think we will be discussing METEOR and cabozantinib, which is not FDA-approved yet. But certainly, I think that is a drug that has a unique mechanism of action, and it’s a little bit different than the VEGF-directed therapies that we have on the market because it also targets c-MET and AXL. These are two pathways that are relevant in progressive RCC. Therefore, I think it makes sense to use cabozantinib in this setting. I think mTOR inhibitors have fallen, especially everolimus, into the salvage setting. It’s been falling from its second- or third-line space because the two phase III trials. With nivolumab, there is CheckMate 025 that we discussed and then there is the METEOR trial studying cabozantinib. Both of these, METEOR and CheckMate 025, used everolimus for a comparator and it was found to be inferior.

Having said that, I think there’s still a role for mTOR inhibitors. If the patient still has a good performance status, obviously, if there’s a clinical trial, I think that would be preferred to enroll the patient. But outside of the context of a clinical trial, if they have not received an mTOR inhibitor, I think it behooves us to try mTOR inhibitors because the patient may have a genomic alteration in their tumor that makes it sensitive to mTOR blockade. And we discussed earlier about the mTOR gene pathway: TSC1, TSC2, and PTEN, and PI3 kinase, etc; those genes may be in 5%, 10% of the tumors. But I think it is still important to not overlook completely the mTOR inhibitors in the salvage setting.
                                                                                                                                                                                                                                                                                                                 Transcript Edited for Clarity
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