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Combination Immunotherapy Treatment Duration in Melanoma Patients

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: Friday, Feb 26, 2016


Transcript:

Keith Flaherty, MD:
Let’s delve into some details. Listeners to this program are just seeing this combination now FDA approved and can look at the clinical trial data but may have a difficult time understanding what their goals should be in terms of the so-called induction period for combination doses. We talked about some of the toxicities, with some more intimidating, some less intimidating in terms of their features. But Rene’s point I think is a good one. We don’t know that four induction doses is absolutely necessary. And I’m wondering what your thoughts are, Jason, in terms of practice.

If you have a patient in front of you who appears to be manifesting toxicity through the second dose, maybe the third dose, how much motivation do you have to try to get to a fourth combination dose, assuming you don’t hit a wall of clear, steroid-requiring autoimmunity? In other words, do you let the patient’s toxicity cool off a bit, maybe delay if you have to, to get that fourth dose in? Or are you comfortable saying, I think we’ve pushed hard and far enough, I’m going to go to the PD-1 maintenance phase in this patient?

Jason Luke, MD, FACP: I guess the former. I’m comfortable when we start to push the envelope that we don’t need to keep going. I think there’s big data series that suggest the patients who start to develop immune-related adverse events should be managed aggressively with immunosuppression, with steroids, and that their long-term outcomes are the same. There’s a slight nuance to what you said, which is that you didn’t actually have to treat them with steroids. It gets a little bit hairy then.

But, certainly for anyone who has toxicity that requires steroids, that’s enough. Now, whether or not to keep giving them PD-1, thereafter, is an interesting question. The trial that he talked about will give us some information about that, but we don’t know the answer so far. But, certainly, definitely, the message has to be, treat the symptoms aggressively with immunosuppression. And thereafter, I’m not excited about giving people with adverse events who require steroids, more ipilimumab. Whether or not they might get more anti-PD-1 antibody, maybe. That depends on the clinical scenario, but I’m not so much trying to push forward.

And I think the phase III trial data support this. Most of the responses happen very quickly. Most of the side effects happen very quickly. If you actually look at these swimmers’ plots, a lot of the patients came off very early from treatment, and yet they’re ongoing in response far later. So, I don’t think that we need to push all these doses. I think it’s sort of a biological pharmacodynamic marker that if the patient is manifesting immune adverse events, then you may have broken tolerance and you’re going to get clinical benefit out over a long period of time.

Jeffrey Weber, MD, PhD: In the CheckMate-069 trial, two-thirds of the patients who had dose-limiting side effects and had to stop, maintained their remission. So it wasn’t all of them. I think that you can get away with giving nivolumab to a patient who’s had ipilimumab and had ipilimumab-related side effects. And I think I’ve shown sufficiently in a small study that you can safely give nivolumab to a patient who’s had an ipilimumab-related toxicity. In CheckMate-064, if you were in arm B where you got ipilimumab first, and you had a dose-limiting toxicity, you could still get it to resolve and move on to your nivolumab doses with a small delay. And generally, the patients did well. So I think you could have combo toxicity, much of which may well be the ipilimumab, stop, recover, and then go to the nivolumab maintenance. I bet you could do that safely. In fact, I perhaps would do that in common practice if I were giving off-protocol combination therapy.

Rene Gonzalez, MD: I would agree with that and what Jason said. I don’t see the need to push the ipilimumab to the limit, and it is a cumulative toxicity. So the more you do it, the more likely you get delayed side effects. Just to clarify, we generally treat the autoimmune events with steroids. The endocrine events often need steroid replacement doses or initially just to get it under control, but the patients come down and are left on a dose of 10 or less, and those patients could potentially get more doses. That’s not necessarily a limiting toxicity.

Jason Luke, MD, FACP: The endocrine effect.

Rene Gonzalez, MD: The endocrine effect. While we’re on that, maybe just bring it up too. Infliximab is a great drug for this diarrhea. It works very quickly. For most patients, it just takes one dose, and you can probably avoid long time (six weeks or more) of high-dose steroids, which might be easier.

Jeffrey Weber, MD, PhD: I agree with Rene. Just to touch on that very briefly, there will be a trial coming up that I helped to write. That’s going to be a small randomized phase II trial of infliximab upfront, just like you said, with a short course of 18 days of prednisone orally versus methylprednisolone at 1 to 2 mgs/kg for a day or two followed by a 30- to 40-day taper. The idea here is to look at duration of diarrhea, duration of symptoms, and the need to go back to high-dose steroids in the infliximab group, which would be a failure. And I think it’s going to be a very interesting trial. It’s open to anyone, ipilimumab/nivolumab combination, lung cancer, melanoma, renal, etcetera. So I think that’s going to be a very good study, and I think it will show that infliximab, just like Rene assumes, works really well.

Keith Flaherty, MD: Let’s close out this session with just maybe one forward-looking comment, Jason. All of this discussion of toxicity is one of the major motivators as to why doctors and patients right now are really enthusiastic about a lot of the PD-1 plus XYZ, ABC combination trials. What’s on your shortlist in terms of emerging results with those types of combinations that viewers of this program might want to keep an eye out looking into next year’s scientific symposia?

Jason Luke, MD, FACP: So one we touched on already was the combination with T-VEC to amplify the immune response. But the other one that we’re very, very interested in is a combination within anti-PD-1 antibody with inhibitors of a molecular called indoleamine dioxygenase (IDO), which is another molecular that’s in the tumor microenvironment. Interestingly, it regulates tryptophan metabolism, and it turns out that T-cells are very exquisitely dependent on just the right amount of tryptophan. That combination in early data presented looks very powerful. Now, we’ll have to see how robust that is as more patients are treated, but the toxicity profile for that combination is almost the same as the anti-PD-1 antibody alone. If we can get anywhere near the kind of benefit we get with the ipilimumab/nivolumab combination with no increase in toxicity, that would be very exciting. And then certainly, there are a lot of other immune checkpoints that are interesting, such as OX40 and all these other ones coming down the pipeline. We don’t know how good those might also be.

Keith Flaherty, MD: I think we’ll close this section by saying clearly, PD-1 antibody-based therapy is established. We have the first combination that clearly shows at least an additive, if not more than an additive effect. But we may be able to really proliferate these types of regimens, and it will be interesting to see if we can really widen the therapeutic index in years to come.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
Let’s delve into some details. Listeners to this program are just seeing this combination now FDA approved and can look at the clinical trial data but may have a difficult time understanding what their goals should be in terms of the so-called induction period for combination doses. We talked about some of the toxicities, with some more intimidating, some less intimidating in terms of their features. But Rene’s point I think is a good one. We don’t know that four induction doses is absolutely necessary. And I’m wondering what your thoughts are, Jason, in terms of practice.

If you have a patient in front of you who appears to be manifesting toxicity through the second dose, maybe the third dose, how much motivation do you have to try to get to a fourth combination dose, assuming you don’t hit a wall of clear, steroid-requiring autoimmunity? In other words, do you let the patient’s toxicity cool off a bit, maybe delay if you have to, to get that fourth dose in? Or are you comfortable saying, I think we’ve pushed hard and far enough, I’m going to go to the PD-1 maintenance phase in this patient?

Jason Luke, MD, FACP: I guess the former. I’m comfortable when we start to push the envelope that we don’t need to keep going. I think there’s big data series that suggest the patients who start to develop immune-related adverse events should be managed aggressively with immunosuppression, with steroids, and that their long-term outcomes are the same. There’s a slight nuance to what you said, which is that you didn’t actually have to treat them with steroids. It gets a little bit hairy then.

But, certainly for anyone who has toxicity that requires steroids, that’s enough. Now, whether or not to keep giving them PD-1, thereafter, is an interesting question. The trial that he talked about will give us some information about that, but we don’t know the answer so far. But, certainly, definitely, the message has to be, treat the symptoms aggressively with immunosuppression. And thereafter, I’m not excited about giving people with adverse events who require steroids, more ipilimumab. Whether or not they might get more anti-PD-1 antibody, maybe. That depends on the clinical scenario, but I’m not so much trying to push forward.

And I think the phase III trial data support this. Most of the responses happen very quickly. Most of the side effects happen very quickly. If you actually look at these swimmers’ plots, a lot of the patients came off very early from treatment, and yet they’re ongoing in response far later. So, I don’t think that we need to push all these doses. I think it’s sort of a biological pharmacodynamic marker that if the patient is manifesting immune adverse events, then you may have broken tolerance and you’re going to get clinical benefit out over a long period of time.

Jeffrey Weber, MD, PhD: In the CheckMate-069 trial, two-thirds of the patients who had dose-limiting side effects and had to stop, maintained their remission. So it wasn’t all of them. I think that you can get away with giving nivolumab to a patient who’s had ipilimumab and had ipilimumab-related side effects. And I think I’ve shown sufficiently in a small study that you can safely give nivolumab to a patient who’s had an ipilimumab-related toxicity. In CheckMate-064, if you were in arm B where you got ipilimumab first, and you had a dose-limiting toxicity, you could still get it to resolve and move on to your nivolumab doses with a small delay. And generally, the patients did well. So I think you could have combo toxicity, much of which may well be the ipilimumab, stop, recover, and then go to the nivolumab maintenance. I bet you could do that safely. In fact, I perhaps would do that in common practice if I were giving off-protocol combination therapy.

Rene Gonzalez, MD: I would agree with that and what Jason said. I don’t see the need to push the ipilimumab to the limit, and it is a cumulative toxicity. So the more you do it, the more likely you get delayed side effects. Just to clarify, we generally treat the autoimmune events with steroids. The endocrine events often need steroid replacement doses or initially just to get it under control, but the patients come down and are left on a dose of 10 or less, and those patients could potentially get more doses. That’s not necessarily a limiting toxicity.

Jason Luke, MD, FACP: The endocrine effect.

Rene Gonzalez, MD: The endocrine effect. While we’re on that, maybe just bring it up too. Infliximab is a great drug for this diarrhea. It works very quickly. For most patients, it just takes one dose, and you can probably avoid long time (six weeks or more) of high-dose steroids, which might be easier.

Jeffrey Weber, MD, PhD: I agree with Rene. Just to touch on that very briefly, there will be a trial coming up that I helped to write. That’s going to be a small randomized phase II trial of infliximab upfront, just like you said, with a short course of 18 days of prednisone orally versus methylprednisolone at 1 to 2 mgs/kg for a day or two followed by a 30- to 40-day taper. The idea here is to look at duration of diarrhea, duration of symptoms, and the need to go back to high-dose steroids in the infliximab group, which would be a failure. And I think it’s going to be a very interesting trial. It’s open to anyone, ipilimumab/nivolumab combination, lung cancer, melanoma, renal, etcetera. So I think that’s going to be a very good study, and I think it will show that infliximab, just like Rene assumes, works really well.

Keith Flaherty, MD: Let’s close out this session with just maybe one forward-looking comment, Jason. All of this discussion of toxicity is one of the major motivators as to why doctors and patients right now are really enthusiastic about a lot of the PD-1 plus XYZ, ABC combination trials. What’s on your shortlist in terms of emerging results with those types of combinations that viewers of this program might want to keep an eye out looking into next year’s scientific symposia?

Jason Luke, MD, FACP: So one we touched on already was the combination with T-VEC to amplify the immune response. But the other one that we’re very, very interested in is a combination within anti-PD-1 antibody with inhibitors of a molecular called indoleamine dioxygenase (IDO), which is another molecular that’s in the tumor microenvironment. Interestingly, it regulates tryptophan metabolism, and it turns out that T-cells are very exquisitely dependent on just the right amount of tryptophan. That combination in early data presented looks very powerful. Now, we’ll have to see how robust that is as more patients are treated, but the toxicity profile for that combination is almost the same as the anti-PD-1 antibody alone. If we can get anywhere near the kind of benefit we get with the ipilimumab/nivolumab combination with no increase in toxicity, that would be very exciting. And then certainly, there are a lot of other immune checkpoints that are interesting, such as OX40 and all these other ones coming down the pipeline. We don’t know how good those might also be.

Keith Flaherty, MD: I think we’ll close this section by saying clearly, PD-1 antibody-based therapy is established. We have the first combination that clearly shows at least an additive, if not more than an additive effect. But we may be able to really proliferate these types of regimens, and it will be interesting to see if we can really widen the therapeutic index in years to come.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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