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Clinical Trial Data Review: Nivolumab Use in RCC

Panelists:Carlos H. Barrios, MD, PUCRS School of Medicine; Daniel HEng, MD, MPH, FRCPC, Tom Baker Cancer Center; Paul Nathan, MBBS, PhD, FRCP, Mount Vernon Cancer Centre; Susanne Osanto, MD, PhD, Leiden University Medical Center; Nizar M. Tannir, MD, FACP, University of Texas MD Anderson Center
Published: Friday, Apr 01, 2016


Transcript:

Daniel Heng, MD, MPH, FRCPC:
So let’s move on to that actually. Now, over the past few months, we’ve seen positive data for nivolumab, a PD-1 inhibitor, also cabozantinib, a VEG, MET, and AXL inhibitor, and we’ll talk about that one in the next segment. But let’s move on to PD-1 inhibitors and nivolumab. Nizar, do you want to talk about that?

Nizar M. Tannir, MD, FACP: Sure. Nivolumab was just FDA approved on November 23rd in the US based on the CheckMate 025 study, which is a large phase III trial of 821 patients, randomized to either nivolumab or everolimus. They chose everolimus as the comparator because this is a trial that recruited patients who had prior VEGFR TKI Therapy. They allowed up to three maximum prior therapies, two VEGFR TKIs. The primary endpoint for the study was overall survival (OS). This is an impressive trial because it was conducted in a fairly reasonable time, and the primary endpoint was met in that patients who were treated with nivolumab had a superior survival to patients who received everolimus. And the hazard ratio was 0.73. That is a 27% reduction in the risk of death for patients who were treated with nivolumab compared to everolimus. Interestingly, in that trial, the progression-free survival (PFS), which was a secondary endpoint, was not different between the two arms, although the objective response rate was in favor of nivolumab, 25% versus 5%. That difference was statistically significant.

So there’s a lot of discussion going around in the circles of renal cell carcinoma doctors as to how we explain the benefit with OS and objective response rate and not PFS. This trial obviously is a good thing for our patients that we have a new agent that has a new mechanism of action that is showing improved survival. And the hope is that not only will it show a survival advantage as it did, but that there will be a plateau at the end of the tail of the Kaplan-Meier curve, that that plateau may be 10%, 15% of the patients who will have durable responses and hopefully a cure.So the CheckMate 025 study is the first trial showing a survival advantage in the salvage setting. Of course, the other trial that showed a survival advantage was the Global ARCC Trial in the first line with temsirolimus in the poor-risk and intermediate-risk patients. So I think this is opening a new field, a new door to immunotherapy in RCC as well as now it is in many other tumor types.

Carlos H. Barrios, MD: This is an important point that I was mentioning before. These patients progressed in four months in both arms. PFS was not different, so that’s something to be explained even though the response rate was a lot higher with nivolumab. The question is, what kind of therapy these patients received afterwards? Were those therapies equal in both arms? What is the immunotherapy doing that actually is making patients to respond better to other therapies that these patients received? So there are a number of things that we have not been recording in clinical trials.

Paul Nathan, MBBS, PhD, FRCP: The other element, too, is that median PFS in this sort of study is a really rubbish endpoint. So the important thing is the landmark analyses. And because of that tail on the curve, and we know we give immunotherapy in the hope of generating durable remission. It’s a minority of patients on the 025 study who may be experiencing that. The two-year upcoming survival analysis will give us that much more follow-up and that’s going to be really important to see whether we get the same sort of shaped curve in RCC as we do with other diseases. But I think it’s really important that we don’t get fixed on median PFS, particularly when looking at immunotherapies. We’re not talking about PFS improvement but the hazard ratio for PFS, or looking at landmark analyses or both. I’m not too worried about a median PFS.

Carlos H. Barrios, MD: I agree. I entirely agree, but the question remains. We don’t know what therapies these patients received after progression and that’s an important question.

Daniel Heng, MD, MPH, FRCPC: It’s something that’s probably going to be presented at another meeting.

Carlos H. Barrios, MD: But the point being that this information is obviously critical, maybe even considering that immunotherapy actually modifies the response to further agents.

Nizar M. Tannir, MD, FACP: I think the concept that immune therapy is beneficial to patients with extending their survival is not just unique to the immune checkpoint inhibitors. If we all remember the sipuleucel-T vaccine in patients with castrate-resistant prostate cancer, there was a four-month improvement in survival. Now, in the CheckMate 025, it was 5.4 months but there, too, there was improvement in OS that was not commensurate or associated with an improvement in PFS or PSA reduction. So I think there is something about the immune system, when you give an immune therapy that revs up the immune system, even if the tumor doesn’t shrink. That patient is no longer under the assault or the aggression of the cancer. They’re living longer even though the tumor may be progressing.

Susanne Osanto, MD, PhD: But I think that the RECIST criteria are completely not useful in immunotherapy. We already know from other tumors, including melanoma, that lesions can become much, much larger if you resect them. If you resect them, you will see infiltration of T-cells and what have you, and if you just applied the RECIST criteria, you would say wow, this is a huge PFS. Stopping treatment or going beyond the formal progression criteria will still give you a remission with strong immunotherapy. It takes quite a while before the immune system is able to detect a tumor. It’s a completely different mode of action, and so you can even have your toxicity and your colitis two years after stopping your monoclonal antibody. So I think we have to look at these set of checkpoint inhibitors.

Nizar M. Tannir, MD, FACP: In a different way.

Susanne Osanto, MD, PhD: In a completely different way.

Paul Nathan, MBBS, PhD, FRCP: I think that’s true for effectively modestly active immunotherapy, when you’ve got highly active immunotherapy; in other words, a sizable proportion of patients, 30%, 40%, 50% of patients having benefit—actually in melanoma again— we find that RECIST criteria are more useful than we thought they were. So it may be that in RCC, obviously, the thing about nivolumab is that it’s really important for that minority of patients who are having benefit. So that’s really important, and hopefully they’ll be durable but it is that minority. We’ve still got 80% of renal patients who are not having durable benefit with immunotherapy. So the key thing for our patients is to develop on that and see if we can increase the proportion of patients having benefit. And whether it’s with some of the things we’re going to talk about soon, combination immunotherapies, I think what we’ll find is that as we push up the proportion of patients who are benefiting, we’re able to see most of that benefit in terms of response rate with RECIST and get less twitched about immune response criteria. I mean these were important when we were treating patients with ipilimumab for melanoma with only 10%, 15% of patients having benefit. As soon as we’re using PD-1 inhibitors or combination checkpoint inhibitors in melanoma, actually you see it with RECIST responses in almost everybody, not everybody but it’s good to get that point [across].

Susanne Osanto, MD, PhD: Well, I do think that melanoma is completely different from kidney cancer. If you test melanoma patients, the T-cells that you are able to detect and to kill destroy class 1 peptides coming from the melanoma cells are easy to get out of any patient, whether it’s the tumor, the lymph node, or the blood. It’s completely different in kidney cancer, so you cannot compare kidney cancer with melanoma.

Paul Nathan, MBBS, PhD, FRCP: No, I wasn’t making a direct comparison but it was more about, first, how we interpret immunotherapy data and I think there are some important lessons because we’ve been through that learning curve with melanoma and it’s about how one interprets those curves. And then secondly, it is just learning from the fact that the way we assess responses changes as you develop more and more active immunotherapy agents. Those were the only paradigms…

Nizar M. Tannir, MD, FACP: But there is new collaborative effort now aimed at coming up with a new system for tumor response in lieu of RECIST that we’ve been commonly using and that’s called the Immune Related Response Assessment. But I think the discordance between objective response rate of 25% versus 5% and the no difference in the PFS still has to be explained. And it could be that there is the concept or observation that we’ve made in melanoma as well as in RCC that is based on the pseudoprogression concept. You know what you mentioned, Susanne, the infiltration of the tumor by the T-cells causing the tumor to increase in size initially, even new lesions appearing that are not really metastatic but more the infiltration in the T-cells. And because perhaps many patients have stopped their therapies or their therapies were stopped because of that progression initially and they were called progressors, but yet they benefited even though that by RECIST they progressed. They benefited and therefore they survived longer.

So I think if you look at the Kaplan-Meier curves, there is really no question about the survival. Dan, if you look at the Kaplan-Meier curves, right, there is the divergence of the tails; the two Kaplan-Meier curves are divergent right from the beginning. So everybody is benefiting, even if by RECIST they have progressive disease. So this therapy is doing something to the immune system that’s making the patient live longer.

Daniel Heng, MD, MPH, FRCPC: It’s certainly very exciting to have these therapies and now nivolumab is FDA approved, I think we have a lot to learn in terms of defining what is progression and how to use it in treatment beyond progression. There’s an abstract on that as well.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Daniel Heng, MD, MPH, FRCPC:
So let’s move on to that actually. Now, over the past few months, we’ve seen positive data for nivolumab, a PD-1 inhibitor, also cabozantinib, a VEG, MET, and AXL inhibitor, and we’ll talk about that one in the next segment. But let’s move on to PD-1 inhibitors and nivolumab. Nizar, do you want to talk about that?

Nizar M. Tannir, MD, FACP: Sure. Nivolumab was just FDA approved on November 23rd in the US based on the CheckMate 025 study, which is a large phase III trial of 821 patients, randomized to either nivolumab or everolimus. They chose everolimus as the comparator because this is a trial that recruited patients who had prior VEGFR TKI Therapy. They allowed up to three maximum prior therapies, two VEGFR TKIs. The primary endpoint for the study was overall survival (OS). This is an impressive trial because it was conducted in a fairly reasonable time, and the primary endpoint was met in that patients who were treated with nivolumab had a superior survival to patients who received everolimus. And the hazard ratio was 0.73. That is a 27% reduction in the risk of death for patients who were treated with nivolumab compared to everolimus. Interestingly, in that trial, the progression-free survival (PFS), which was a secondary endpoint, was not different between the two arms, although the objective response rate was in favor of nivolumab, 25% versus 5%. That difference was statistically significant.

So there’s a lot of discussion going around in the circles of renal cell carcinoma doctors as to how we explain the benefit with OS and objective response rate and not PFS. This trial obviously is a good thing for our patients that we have a new agent that has a new mechanism of action that is showing improved survival. And the hope is that not only will it show a survival advantage as it did, but that there will be a plateau at the end of the tail of the Kaplan-Meier curve, that that plateau may be 10%, 15% of the patients who will have durable responses and hopefully a cure.So the CheckMate 025 study is the first trial showing a survival advantage in the salvage setting. Of course, the other trial that showed a survival advantage was the Global ARCC Trial in the first line with temsirolimus in the poor-risk and intermediate-risk patients. So I think this is opening a new field, a new door to immunotherapy in RCC as well as now it is in many other tumor types.

Carlos H. Barrios, MD: This is an important point that I was mentioning before. These patients progressed in four months in both arms. PFS was not different, so that’s something to be explained even though the response rate was a lot higher with nivolumab. The question is, what kind of therapy these patients received afterwards? Were those therapies equal in both arms? What is the immunotherapy doing that actually is making patients to respond better to other therapies that these patients received? So there are a number of things that we have not been recording in clinical trials.

Paul Nathan, MBBS, PhD, FRCP: The other element, too, is that median PFS in this sort of study is a really rubbish endpoint. So the important thing is the landmark analyses. And because of that tail on the curve, and we know we give immunotherapy in the hope of generating durable remission. It’s a minority of patients on the 025 study who may be experiencing that. The two-year upcoming survival analysis will give us that much more follow-up and that’s going to be really important to see whether we get the same sort of shaped curve in RCC as we do with other diseases. But I think it’s really important that we don’t get fixed on median PFS, particularly when looking at immunotherapies. We’re not talking about PFS improvement but the hazard ratio for PFS, or looking at landmark analyses or both. I’m not too worried about a median PFS.

Carlos H. Barrios, MD: I agree. I entirely agree, but the question remains. We don’t know what therapies these patients received after progression and that’s an important question.

Daniel Heng, MD, MPH, FRCPC: It’s something that’s probably going to be presented at another meeting.

Carlos H. Barrios, MD: But the point being that this information is obviously critical, maybe even considering that immunotherapy actually modifies the response to further agents.

Nizar M. Tannir, MD, FACP: I think the concept that immune therapy is beneficial to patients with extending their survival is not just unique to the immune checkpoint inhibitors. If we all remember the sipuleucel-T vaccine in patients with castrate-resistant prostate cancer, there was a four-month improvement in survival. Now, in the CheckMate 025, it was 5.4 months but there, too, there was improvement in OS that was not commensurate or associated with an improvement in PFS or PSA reduction. So I think there is something about the immune system, when you give an immune therapy that revs up the immune system, even if the tumor doesn’t shrink. That patient is no longer under the assault or the aggression of the cancer. They’re living longer even though the tumor may be progressing.

Susanne Osanto, MD, PhD: But I think that the RECIST criteria are completely not useful in immunotherapy. We already know from other tumors, including melanoma, that lesions can become much, much larger if you resect them. If you resect them, you will see infiltration of T-cells and what have you, and if you just applied the RECIST criteria, you would say wow, this is a huge PFS. Stopping treatment or going beyond the formal progression criteria will still give you a remission with strong immunotherapy. It takes quite a while before the immune system is able to detect a tumor. It’s a completely different mode of action, and so you can even have your toxicity and your colitis two years after stopping your monoclonal antibody. So I think we have to look at these set of checkpoint inhibitors.

Nizar M. Tannir, MD, FACP: In a different way.

Susanne Osanto, MD, PhD: In a completely different way.

Paul Nathan, MBBS, PhD, FRCP: I think that’s true for effectively modestly active immunotherapy, when you’ve got highly active immunotherapy; in other words, a sizable proportion of patients, 30%, 40%, 50% of patients having benefit—actually in melanoma again— we find that RECIST criteria are more useful than we thought they were. So it may be that in RCC, obviously, the thing about nivolumab is that it’s really important for that minority of patients who are having benefit. So that’s really important, and hopefully they’ll be durable but it is that minority. We’ve still got 80% of renal patients who are not having durable benefit with immunotherapy. So the key thing for our patients is to develop on that and see if we can increase the proportion of patients having benefit. And whether it’s with some of the things we’re going to talk about soon, combination immunotherapies, I think what we’ll find is that as we push up the proportion of patients who are benefiting, we’re able to see most of that benefit in terms of response rate with RECIST and get less twitched about immune response criteria. I mean these were important when we were treating patients with ipilimumab for melanoma with only 10%, 15% of patients having benefit. As soon as we’re using PD-1 inhibitors or combination checkpoint inhibitors in melanoma, actually you see it with RECIST responses in almost everybody, not everybody but it’s good to get that point [across].

Susanne Osanto, MD, PhD: Well, I do think that melanoma is completely different from kidney cancer. If you test melanoma patients, the T-cells that you are able to detect and to kill destroy class 1 peptides coming from the melanoma cells are easy to get out of any patient, whether it’s the tumor, the lymph node, or the blood. It’s completely different in kidney cancer, so you cannot compare kidney cancer with melanoma.

Paul Nathan, MBBS, PhD, FRCP: No, I wasn’t making a direct comparison but it was more about, first, how we interpret immunotherapy data and I think there are some important lessons because we’ve been through that learning curve with melanoma and it’s about how one interprets those curves. And then secondly, it is just learning from the fact that the way we assess responses changes as you develop more and more active immunotherapy agents. Those were the only paradigms…

Nizar M. Tannir, MD, FACP: But there is new collaborative effort now aimed at coming up with a new system for tumor response in lieu of RECIST that we’ve been commonly using and that’s called the Immune Related Response Assessment. But I think the discordance between objective response rate of 25% versus 5% and the no difference in the PFS still has to be explained. And it could be that there is the concept or observation that we’ve made in melanoma as well as in RCC that is based on the pseudoprogression concept. You know what you mentioned, Susanne, the infiltration of the tumor by the T-cells causing the tumor to increase in size initially, even new lesions appearing that are not really metastatic but more the infiltration in the T-cells. And because perhaps many patients have stopped their therapies or their therapies were stopped because of that progression initially and they were called progressors, but yet they benefited even though that by RECIST they progressed. They benefited and therefore they survived longer.

So I think if you look at the Kaplan-Meier curves, there is really no question about the survival. Dan, if you look at the Kaplan-Meier curves, right, there is the divergence of the tails; the two Kaplan-Meier curves are divergent right from the beginning. So everybody is benefiting, even if by RECIST they have progressive disease. So this therapy is doing something to the immune system that’s making the patient live longer.

Daniel Heng, MD, MPH, FRCPC: It’s certainly very exciting to have these therapies and now nivolumab is FDA approved, I think we have a lot to learn in terms of defining what is progression and how to use it in treatment beyond progression. There’s an abstract on that as well.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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