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Combination Ipilimumab/Nivolumab in Metastatic Melanoma

Panelists: Axel Hauschild, MD, University Hospital Schleswig-Holstein; Michael A. Davies, MD, PhD UT MD Anderson Cancer Center; Jason J. Luke, MD, FACP, University of Chicago; Caroline Robert, MD, PhD Gustave-Roussy; Merrick I. Ross, MD UT MD Anderson Cancer Center
Published: Friday, Dec 21, 2018



Transcript: 

Axel Hauschild, MD:
In particular for ipilimumab and nivolumab, you mentioned the CheckMate 067 that brings the combination to us and the market. We have seen an update as a late-breaking abstract at this year’s ESMO [European Society for Medical Oncology] Congress. The question is, are you impressed about the 4-year survival data, Jason?

Jason J. Luke, MD, FACP: I am. I think we’re seeing that the data are starting to hold up over time. The thing about using a doublet checkpoint blockade is that the toxicity profile of using the 2 drugs together comes to mind, which has generated this new term to think about time off treatment. And so, as the survival is holding up over time, most of those patients are no longer requiring therapy—or many of them are not. I think that’s something that we’re going to start to think about, in terms of use and impact on the health system. Is there value to getting patients to a place where you don’t actually have to continue to treat them over time? I think there are a lot of arguments on the optimal dosing of ipilimumab, and I think that’s something that we’ll see.

There was also an abstract at ESMO that looked at 3 mg/kg versus 1 mg/kg in conjunction with nivolumab. As we start to see long-term survivorship in these trials going out further, and we extrapolate that into our clinical practice, when we try to emphasize or identify for each patient, what is the best way to get them there? It’s so exciting to think about this—that it’s 4-year survival and it’s 40%. That’s what we’re going to accept as minimal, right? And we are only going to move forward from there.

Axel Hauschild, MD: Mike, although the 4-year survival looks pretty good, there is still no statistical difference in overall survival. I think the difference is 7%, but it is not statistically significant., whereas there’s a difference in progression-free survival. It was surprising to see that the 4-year duration of response for the combination is exciting, right? Everybody would agree. But the median has not been reached for nivolumab alone. Isn’t the biggest surprise of this clinical trial how good patients who were treated with nivolumab alone are doing? Or is this because these patients with nivolumab alone received more subsequent salvage therapies, eventually ipilimumab or combinations.? Is this the reason why they are doing so well? It’s something that needs to be explored, right?

Michael A. Davies, MD, PhD: If we could go back in time, what really would have been powerful in CheckMate 067 would have been to have some control of what the next therapy was. The reality is, comparing ipilimumab-nivolumab versus nivolumab alone in terms of the initial response rates is asking, which option do you get better initial activity with? But if your goal is long-term survival, it’s really a question of, is it better to give ipilimumab and nivolumab together, or is it better to use them sequentially, and again, use the second agent only if needed?

What we’re learning from the presentations sort of makes sense. The resistance mechanisms to PD-1 [programmed cell death protein 1] and CTLA4 are not the same. Therefore, a patient who had not responded to CTLA4 therapy could respond to PD-1 therapy. In less published data, we’ve seen that the patients who don’t respond to PD-1 therapy or progress on PD-1 therapy can respond to CTLA4 therapy. Actually, Jason presented data at ASCO [American Society of Clinical Oncology] this year about a really intriguing trial looking at a CTLA-4 and PD-1 combination in patients who progressed on PD-1 therapy. These were early results, but they actually looked quite promising. Interestingly, it also looked like the tolerability in the second-line setting might be better than in the frontline setting.

Jason J. Luke, MD, FACP: Yes. There was also a previous phase II trial that looked at the sequencing of nivolumab to ipilimumab and ipilimumab to nivolumab. That study, CheckMate 064, had a hard switch that was criticized quite a bit. Yet I think this helps inform us on this question of sequencing therapy. In that study, if you went with nivolumab and then ipilimumab, your 6-month aggregate outcome was approximately what you would get from using ipilimumab-nivolumab up front. In that context, we were interested in looking at the activity of the PD-1/CTLA-4 low-dose combination in the second-line setting after PD-1 failure as an immediate rollover. And so when we did that, we saw that the response rate was 45% in the second-line setting. So you imagine a scenario in which everyone is doing super awesome on nivolumab, and they’re getting a 40% 4-year survival. But for those who don’t, you can still get a 45% response in the second-line setting. We’ll see how that holds up over time. That’s an exciting paradigm, in which we can start to reduce toxicity and limit exposure to other agents until a time when the patient really needs them.

Merrick I. Ross, MD: Jason, in your clinical practice outside a clinical trial, let’s say that the patient is on single-agent nivolumab and has a response but then starts to progress. Do you switch them to ipilimumab, or do you just add ipilimumab and continue the nivolumab? And if you add ipilimumab, do you add the 1-mg dose or use the 3-mg dose?

Jason J. Luke, MD, FACP: Those are all good questions. In the United States, we are fortunate that we can do these things. So what we commonly do is just add ipilimumab and keep going.

Merrick I. Ross, MD: So you could continue the nivolumab?

Jason J. Luke, MD, FACP: We continue the nivolumab, and we add the ipilimumab.

Merrick I. Ross, MD: Then would you use 1 mg of ipilimumab, or would you switch and change nivolumab to 1 mg and add 3 mg?

Jason J. Luke, MD, FACP: For common practice, for reasons that are unclear to me, we run into insurance issues if we try to use the lower dose, even though this would save the insurer money.

Merrick I. Ross, MD: It’s crazy.

Jason J. Luke, MD, FACP: For some reason, they give us a hard time about not using the approved dose. So commonly, depending on what’s going on, we...

Axel Hauschild, MD: I have a follow-up question on the lower dose. CheckMate 511 has been presented, and I think this is a very important clinical trial for the community doctors and academic centers. This was a full dose of ipilimumab, as approved—3 mg/kg and the low-dose of nivolumab, 1 mg/kg. This was 1 group. The other group had the opposite dosing schedule, which means a low dose of ipilimumab and the full dose of nivolumab. The results are showing the same efficacy but much less toxicity for the low-dose ipilimumab scheme. So is this immediately practice changing, more or less? At least in the United States, it’s not unlikely that very many physicians would change, right?

Jason J. Luke, MD, FACP: Well, I think the data has to penetrate out into the community first. I mean, we’re talking about an abstract that’s presented. I don’t know that everyone knows about it yet. But I do think that as we’re discussing sort of responsiveness in the second-line with a lower dose, and now as frontline data are showing a lower dose and similar kinds of response rates, I do think that needs to be the shift. Over time, that is only practical. You’re saving a lot of toxicity and maintaining the benefit. I think that’s probably what we should be doing.

Michael A. Davies, MD, PhD: The caveat is thinking back to the study of ipilimumab at 10 mg/kg versus 3 mg/kg, in which there was no difference in progression-free survival but an unexpected difference in overall survival. This is really interesting initial data. We’re certainly going to have to keep following this, in terms of what happens over time. Although we’re talking about which therapy is right to start with, I think we’d love to get to the point where we have some type of marker, whether it’s clinical, molecular, or immune, that helps guide you in picking between those therapies.

Jason J. Luke, MD, FACP: Well, to that point, I would actually add a caveat to what I said. In my practice, I usually start with a PD-1 monotherapy. There are patients for whom I do not do that. Who are they? They are patients with brain metastases, high LDH [lactic acid dehydrogenase], and rapid progression. In those scenarios, I’m looking for immediate response. So those would actually be patients, especially the ones with brain metastases given the data from multiple groups, for whom I probably would not drop the dose of ipilimumab.


Transcript Edited for Clarity
 

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Transcript: 

Axel Hauschild, MD:
In particular for ipilimumab and nivolumab, you mentioned the CheckMate 067 that brings the combination to us and the market. We have seen an update as a late-breaking abstract at this year’s ESMO [European Society for Medical Oncology] Congress. The question is, are you impressed about the 4-year survival data, Jason?

Jason J. Luke, MD, FACP: I am. I think we’re seeing that the data are starting to hold up over time. The thing about using a doublet checkpoint blockade is that the toxicity profile of using the 2 drugs together comes to mind, which has generated this new term to think about time off treatment. And so, as the survival is holding up over time, most of those patients are no longer requiring therapy—or many of them are not. I think that’s something that we’re going to start to think about, in terms of use and impact on the health system. Is there value to getting patients to a place where you don’t actually have to continue to treat them over time? I think there are a lot of arguments on the optimal dosing of ipilimumab, and I think that’s something that we’ll see.

There was also an abstract at ESMO that looked at 3 mg/kg versus 1 mg/kg in conjunction with nivolumab. As we start to see long-term survivorship in these trials going out further, and we extrapolate that into our clinical practice, when we try to emphasize or identify for each patient, what is the best way to get them there? It’s so exciting to think about this—that it’s 4-year survival and it’s 40%. That’s what we’re going to accept as minimal, right? And we are only going to move forward from there.

Axel Hauschild, MD: Mike, although the 4-year survival looks pretty good, there is still no statistical difference in overall survival. I think the difference is 7%, but it is not statistically significant., whereas there’s a difference in progression-free survival. It was surprising to see that the 4-year duration of response for the combination is exciting, right? Everybody would agree. But the median has not been reached for nivolumab alone. Isn’t the biggest surprise of this clinical trial how good patients who were treated with nivolumab alone are doing? Or is this because these patients with nivolumab alone received more subsequent salvage therapies, eventually ipilimumab or combinations.? Is this the reason why they are doing so well? It’s something that needs to be explored, right?

Michael A. Davies, MD, PhD: If we could go back in time, what really would have been powerful in CheckMate 067 would have been to have some control of what the next therapy was. The reality is, comparing ipilimumab-nivolumab versus nivolumab alone in terms of the initial response rates is asking, which option do you get better initial activity with? But if your goal is long-term survival, it’s really a question of, is it better to give ipilimumab and nivolumab together, or is it better to use them sequentially, and again, use the second agent only if needed?

What we’re learning from the presentations sort of makes sense. The resistance mechanisms to PD-1 [programmed cell death protein 1] and CTLA4 are not the same. Therefore, a patient who had not responded to CTLA4 therapy could respond to PD-1 therapy. In less published data, we’ve seen that the patients who don’t respond to PD-1 therapy or progress on PD-1 therapy can respond to CTLA4 therapy. Actually, Jason presented data at ASCO [American Society of Clinical Oncology] this year about a really intriguing trial looking at a CTLA-4 and PD-1 combination in patients who progressed on PD-1 therapy. These were early results, but they actually looked quite promising. Interestingly, it also looked like the tolerability in the second-line setting might be better than in the frontline setting.

Jason J. Luke, MD, FACP: Yes. There was also a previous phase II trial that looked at the sequencing of nivolumab to ipilimumab and ipilimumab to nivolumab. That study, CheckMate 064, had a hard switch that was criticized quite a bit. Yet I think this helps inform us on this question of sequencing therapy. In that study, if you went with nivolumab and then ipilimumab, your 6-month aggregate outcome was approximately what you would get from using ipilimumab-nivolumab up front. In that context, we were interested in looking at the activity of the PD-1/CTLA-4 low-dose combination in the second-line setting after PD-1 failure as an immediate rollover. And so when we did that, we saw that the response rate was 45% in the second-line setting. So you imagine a scenario in which everyone is doing super awesome on nivolumab, and they’re getting a 40% 4-year survival. But for those who don’t, you can still get a 45% response in the second-line setting. We’ll see how that holds up over time. That’s an exciting paradigm, in which we can start to reduce toxicity and limit exposure to other agents until a time when the patient really needs them.

Merrick I. Ross, MD: Jason, in your clinical practice outside a clinical trial, let’s say that the patient is on single-agent nivolumab and has a response but then starts to progress. Do you switch them to ipilimumab, or do you just add ipilimumab and continue the nivolumab? And if you add ipilimumab, do you add the 1-mg dose or use the 3-mg dose?

Jason J. Luke, MD, FACP: Those are all good questions. In the United States, we are fortunate that we can do these things. So what we commonly do is just add ipilimumab and keep going.

Merrick I. Ross, MD: So you could continue the nivolumab?

Jason J. Luke, MD, FACP: We continue the nivolumab, and we add the ipilimumab.

Merrick I. Ross, MD: Then would you use 1 mg of ipilimumab, or would you switch and change nivolumab to 1 mg and add 3 mg?

Jason J. Luke, MD, FACP: For common practice, for reasons that are unclear to me, we run into insurance issues if we try to use the lower dose, even though this would save the insurer money.

Merrick I. Ross, MD: It’s crazy.

Jason J. Luke, MD, FACP: For some reason, they give us a hard time about not using the approved dose. So commonly, depending on what’s going on, we...

Axel Hauschild, MD: I have a follow-up question on the lower dose. CheckMate 511 has been presented, and I think this is a very important clinical trial for the community doctors and academic centers. This was a full dose of ipilimumab, as approved—3 mg/kg and the low-dose of nivolumab, 1 mg/kg. This was 1 group. The other group had the opposite dosing schedule, which means a low dose of ipilimumab and the full dose of nivolumab. The results are showing the same efficacy but much less toxicity for the low-dose ipilimumab scheme. So is this immediately practice changing, more or less? At least in the United States, it’s not unlikely that very many physicians would change, right?

Jason J. Luke, MD, FACP: Well, I think the data has to penetrate out into the community first. I mean, we’re talking about an abstract that’s presented. I don’t know that everyone knows about it yet. But I do think that as we’re discussing sort of responsiveness in the second-line with a lower dose, and now as frontline data are showing a lower dose and similar kinds of response rates, I do think that needs to be the shift. Over time, that is only practical. You’re saving a lot of toxicity and maintaining the benefit. I think that’s probably what we should be doing.

Michael A. Davies, MD, PhD: The caveat is thinking back to the study of ipilimumab at 10 mg/kg versus 3 mg/kg, in which there was no difference in progression-free survival but an unexpected difference in overall survival. This is really interesting initial data. We’re certainly going to have to keep following this, in terms of what happens over time. Although we’re talking about which therapy is right to start with, I think we’d love to get to the point where we have some type of marker, whether it’s clinical, molecular, or immune, that helps guide you in picking between those therapies.

Jason J. Luke, MD, FACP: Well, to that point, I would actually add a caveat to what I said. In my practice, I usually start with a PD-1 monotherapy. There are patients for whom I do not do that. Who are they? They are patients with brain metastases, high LDH [lactic acid dehydrogenase], and rapid progression. In those scenarios, I’m looking for immediate response. So those would actually be patients, especially the ones with brain metastases given the data from multiple groups, for whom I probably would not drop the dose of ipilimumab.


Transcript Edited for Clarity
 
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