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Checkpoint Inhibitors: Combination Therapy in Melanoma

Panelists:Keith T. Flaherty, MD, Massachusetts General Hospital; Rene Gonzalez, MD, University of Colorado Melanoma Research Clinics; Jason J. Luke, MD, FACP, University of Chicago Medicine; Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center
Published: Monday, Feb 22, 2016


Transcript:

Keith Flaherty, MD:
With ipilimumab and nivolumab now FDA approved, you look at the data that got it across the finish line. It’s a reasonably immature study, but it nailed a couple of points down. The response rate and the progression-free survival, at least with the median follow-up of a year, are superior with combination therapy compared with the protocol standard control of ipilimumab. But this may also be the case compared to PD-1 monotherapy. You see better disease controlling parameters. How would you summarize to a patient in front of you what the value of that therapy is in terms of why it is that you would nominate that over PD-1 monotherapy, as, I think we all agree, for the vast majority of patients, is the treatment standard.

Jason Luke, MD, FACP: Well, I think it’s almost a gut thing. You look at that data, and it just looks more powerful. You need response, you want to go for it right now. I actually think we need the longer-term follow-up to really look at what happens in those patients. I think it is likely that the combination CTLA4 and PD-1 is going to lead a longer overall survival relative to PD-1 alone. I agree with that. I just think that the toxicity profile associated with that is substantial.

And so the question becomes can we find patients where we don’t have to expose them to the toxicity. We don’t know how to answer it yet. So, for the patient who’s in front of me, I explain both. This therapy, it’s highly effective, low toxicity. We can add ipilimumab on top of that. The question is, do we need to? And we really don’t have that answer yet, and I think we need to find that out. I think we also need to find out if you give the combination as second-line therapy, is it as effective as it would have been as frontline therapy? Because then, could you have saved the patient from that exposure? But in the current time, I think it’s a conversation about whether the patient is comfortable with the idea that you’re not going to just throw the kitchen sink at them immediately. And I think different patients have different perspectives on this.

Some people go in scared to death that the doctor is going to give them chemo and their hair is going to fall out and it’s going to be awful, and other people come in saying, you know, I don’t care what it is, just do the maximum to me immediately to treat the cancer. And that’s probably a different conversation with different patients. I know in my practice I’m more comfortable with anti-PD-1 as monotherapy as frontline therapy except in some patients, such as young female patient with brain metastases, I’m worried that we’re not going to have much time to try all these things. So, it’s kitchen sink time. But in most patients where that’s not the case, I feel more comfortable.

Keith Flaherty, MD: That’s one end of the spectrum. Even having relatively immature data, showing clearly a more powerful upfront effect response rate and better overall disease control. I’d say this is clearest in the high-disease burden patient who cannot afford to go through sequential therapy. And in every one of our practices we might quote a slightly different number in terms of the percentage of those patents. But, Rene, I’m interested in your thoughts. You’re someone who’s given high-dose IL-2 over the years, as have I. But I’m wondering how do you look at your historical high-dose IL-2 candidates in the face of this therapy? In other words, young, highly motivated but asymptomatic, low disease burden and where toxicity, in your discussion with them, is really dropping down the list of priorities. Does this have a place for those patients based on the current evidence?

Rene Gonzalez, MD: Yeah, I think it definitely does. Patients to whom we would have given high-dose IL-2 in the past are now getting this. It looks like a highly effective and maybe our go-to regimen. There are a couple things about it though. One is we don’t really know the dose. These doses were just basically put together—the two individual doses of the drugs—and I’m not sure we need to give that dose, and for how long. So, that’s something to figure out there.

The other thing is the toxicity. Yes, it’s toxic. I think it’s even more toxic than the higher doses of ipilimumab. It’s the same sort of thing, but they’re more frequent and seem to be more severe. By that I mean, if you’ve got grade 3 diarrhea, you’ve got grade 3 diarrhea. But if you’re going seven times a day to the bathroom, it’s different than if you’re going 20 times. And so it seems to be more severe. But the flip side of that is before these drugs, the survival for melanoma was nine months, and now potentially, it’s years. So to me, it’s worth the toxicity.

Jeffrey Weber, MD, PhD: But I think Rene makes a very good point. One of the dirty little secrets about using combination ipilimumab plus nivolumab is, we all agree that the responses are deeper. The spider plots show that very steep immediate rapid response which makes it the perfect therapy for a BRAF wild-type patient who has aggressive, high-LDH bulk rapidly growing disease, or even a BRAF mutated patient.

Remember, there’s no difference. James Larkin showed in a recent article that there’s no difference in BRAF-mutated and BRAF wild-type patients in how well they respond to the combination. But the dirty little secret is—I think Rene’s right—the toxicity is deeper, quicker, and more intense. And I’ve seen some pretty wild side effects in the patients getting the combination therapy. I have a mixed view on this. I agree with what Rene said. On the other hand, much of the toxicity is biochemical, such as grade 3 hyperamylasemia with no symptoms. I’m not sure what to do with that.

In fact, I recently put together an adjuvant trial where the FDA gave us the IND and allowed us to take those with grade 3 amylase and lipase elevations—I wouldn’t say ignore it—but we just wait until it comes down and then keep treating, and the patients have done fine. That accounts for a good bit of the toxicity. AST and ALT elevations account for another good bit, but you’re probably looking at a 14% rate of grade 3/4 colitis and diarrhea, and that’s a big time problem. And if you add the diarrhea and the colitis together, which in the toxicity ratings are often separate. They overlap, so it’s probably a little more. Those patients got pretty darn sick.

So, yes, I absolutely agree the toxicity is significant. Much of it is biochemical. I think the combination is the treatment of choice for anyone with rapidly progressive, high-LDH, aggressive, symptomatic disease. I also think it’s a great neoadjuvant therapy, as we discussed before. It’s got a 50-plus percent response rate, which is really what you want in a neoadjuvant therapy. And it’s what you want in a therapy for those with rapidly progressive disease.

Perhaps you could get away with nivolumab or pembrolizumab alone in indolent disease. I would venture a bet that the patients with what we think of as indolent, low burden disease, tend to be the PD-L1-positive patients with the hot tumors, with the T-cell infiltrate. They’re going to do well with whatever you give them. It’s the rapid progressors, the high LDH, that have the cold tumors, where you need the ipilimumab and the nivolumab. So, those are the patients I’m going to give the combination to. And I’m feeling a little more comfortable with the combination these days for many patients in general, but I agree with the previous comments. In a patient with low burden disease, low LDH that’s not rapidly progressive, you can probably get away with PD-1 alone and do very well.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
With ipilimumab and nivolumab now FDA approved, you look at the data that got it across the finish line. It’s a reasonably immature study, but it nailed a couple of points down. The response rate and the progression-free survival, at least with the median follow-up of a year, are superior with combination therapy compared with the protocol standard control of ipilimumab. But this may also be the case compared to PD-1 monotherapy. You see better disease controlling parameters. How would you summarize to a patient in front of you what the value of that therapy is in terms of why it is that you would nominate that over PD-1 monotherapy, as, I think we all agree, for the vast majority of patients, is the treatment standard.

Jason Luke, MD, FACP: Well, I think it’s almost a gut thing. You look at that data, and it just looks more powerful. You need response, you want to go for it right now. I actually think we need the longer-term follow-up to really look at what happens in those patients. I think it is likely that the combination CTLA4 and PD-1 is going to lead a longer overall survival relative to PD-1 alone. I agree with that. I just think that the toxicity profile associated with that is substantial.

And so the question becomes can we find patients where we don’t have to expose them to the toxicity. We don’t know how to answer it yet. So, for the patient who’s in front of me, I explain both. This therapy, it’s highly effective, low toxicity. We can add ipilimumab on top of that. The question is, do we need to? And we really don’t have that answer yet, and I think we need to find that out. I think we also need to find out if you give the combination as second-line therapy, is it as effective as it would have been as frontline therapy? Because then, could you have saved the patient from that exposure? But in the current time, I think it’s a conversation about whether the patient is comfortable with the idea that you’re not going to just throw the kitchen sink at them immediately. And I think different patients have different perspectives on this.

Some people go in scared to death that the doctor is going to give them chemo and their hair is going to fall out and it’s going to be awful, and other people come in saying, you know, I don’t care what it is, just do the maximum to me immediately to treat the cancer. And that’s probably a different conversation with different patients. I know in my practice I’m more comfortable with anti-PD-1 as monotherapy as frontline therapy except in some patients, such as young female patient with brain metastases, I’m worried that we’re not going to have much time to try all these things. So, it’s kitchen sink time. But in most patients where that’s not the case, I feel more comfortable.

Keith Flaherty, MD: That’s one end of the spectrum. Even having relatively immature data, showing clearly a more powerful upfront effect response rate and better overall disease control. I’d say this is clearest in the high-disease burden patient who cannot afford to go through sequential therapy. And in every one of our practices we might quote a slightly different number in terms of the percentage of those patents. But, Rene, I’m interested in your thoughts. You’re someone who’s given high-dose IL-2 over the years, as have I. But I’m wondering how do you look at your historical high-dose IL-2 candidates in the face of this therapy? In other words, young, highly motivated but asymptomatic, low disease burden and where toxicity, in your discussion with them, is really dropping down the list of priorities. Does this have a place for those patients based on the current evidence?

Rene Gonzalez, MD: Yeah, I think it definitely does. Patients to whom we would have given high-dose IL-2 in the past are now getting this. It looks like a highly effective and maybe our go-to regimen. There are a couple things about it though. One is we don’t really know the dose. These doses were just basically put together—the two individual doses of the drugs—and I’m not sure we need to give that dose, and for how long. So, that’s something to figure out there.

The other thing is the toxicity. Yes, it’s toxic. I think it’s even more toxic than the higher doses of ipilimumab. It’s the same sort of thing, but they’re more frequent and seem to be more severe. By that I mean, if you’ve got grade 3 diarrhea, you’ve got grade 3 diarrhea. But if you’re going seven times a day to the bathroom, it’s different than if you’re going 20 times. And so it seems to be more severe. But the flip side of that is before these drugs, the survival for melanoma was nine months, and now potentially, it’s years. So to me, it’s worth the toxicity.

Jeffrey Weber, MD, PhD: But I think Rene makes a very good point. One of the dirty little secrets about using combination ipilimumab plus nivolumab is, we all agree that the responses are deeper. The spider plots show that very steep immediate rapid response which makes it the perfect therapy for a BRAF wild-type patient who has aggressive, high-LDH bulk rapidly growing disease, or even a BRAF mutated patient.

Remember, there’s no difference. James Larkin showed in a recent article that there’s no difference in BRAF-mutated and BRAF wild-type patients in how well they respond to the combination. But the dirty little secret is—I think Rene’s right—the toxicity is deeper, quicker, and more intense. And I’ve seen some pretty wild side effects in the patients getting the combination therapy. I have a mixed view on this. I agree with what Rene said. On the other hand, much of the toxicity is biochemical, such as grade 3 hyperamylasemia with no symptoms. I’m not sure what to do with that.

In fact, I recently put together an adjuvant trial where the FDA gave us the IND and allowed us to take those with grade 3 amylase and lipase elevations—I wouldn’t say ignore it—but we just wait until it comes down and then keep treating, and the patients have done fine. That accounts for a good bit of the toxicity. AST and ALT elevations account for another good bit, but you’re probably looking at a 14% rate of grade 3/4 colitis and diarrhea, and that’s a big time problem. And if you add the diarrhea and the colitis together, which in the toxicity ratings are often separate. They overlap, so it’s probably a little more. Those patients got pretty darn sick.

So, yes, I absolutely agree the toxicity is significant. Much of it is biochemical. I think the combination is the treatment of choice for anyone with rapidly progressive, high-LDH, aggressive, symptomatic disease. I also think it’s a great neoadjuvant therapy, as we discussed before. It’s got a 50-plus percent response rate, which is really what you want in a neoadjuvant therapy. And it’s what you want in a therapy for those with rapidly progressive disease.

Perhaps you could get away with nivolumab or pembrolizumab alone in indolent disease. I would venture a bet that the patients with what we think of as indolent, low burden disease, tend to be the PD-L1-positive patients with the hot tumors, with the T-cell infiltrate. They’re going to do well with whatever you give them. It’s the rapid progressors, the high LDH, that have the cold tumors, where you need the ipilimumab and the nivolumab. So, those are the patients I’m going to give the combination to. And I’m feeling a little more comfortable with the combination these days for many patients in general, but I agree with the previous comments. In a patient with low burden disease, low LDH that’s not rapidly progressive, you can probably get away with PD-1 alone and do very well.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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