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Melanoma: Considerations in Checkpoint Inhibition

Panelists:Keith T. Flaherty, MD Massachusetts General Hospital;Georgina Long, BSc, MBBS, FRACP, Melanoma Institute of Australia;Jason J. Luke, MD, FACP, University of Chicago;Jeffrey S. Weber, MD, NYU Langone Medical Center;Jonathan S. Zager, MD, Moffitt Cancer Center
Published: Wednesday, Sep 14, 2016



Transcript:

Keith T. Flaherty, MD:
Let’s switch gears. Thinking about immune checkpoint therapy, we have this historical artifact of ipilimumab being introduced first; PD-1 antibodies being evaluated in ipilimumab refractory patients and associated with response percentages, some of which are in FDA labels. Then, more recently, you get PD-1 inhibitor monotherapy data which, of course, is what we think about when we’re talking to patients about predicted outcome. Jason, you’ve got a patient in front of you—let’s make it easy and say they’re BRAF wild-type—and you’re preparing to have the discussion with the patient about PD-1 monotherapy versus PD-1/CTLA4. But, hold for a moment on that combination part. How do you describe the upsides and downsides of PD-1 antibody monotherapy?

Jason J. Luke, MD: Well, the way I usually describe it to patients is I take them through the historical progression. I actually start from IL-2, and then go to ipilimumab to talk about the progression that we’ve been making with serially increased response rates and durable benefit over time. And when you get to PD-1, you then identify that now you have a 40% response, relative to prior 10%. It looks like there’s a durable amount, at least like maybe in the 30% range, a number of patients are out a long time. And you actually decrease the side effect profile relative to prior immunotherapy approaches. It’s a pretty convincing argument that this is the right thing to do. But, I think there’s really no debate in the field now that in the immunotherapy space, PD-1 antibodies are now the core of immunotherapy in melanoma, and probably more cancers actually. So, I think that that part is very easy. The question then is going on to the combinations, so how you do that?

Keith T. Flaherty, MD: A nice summary on the efficacy side. But, when you’re talking about toxicity, the problem with the discussion if you just go based on lifting data out of a New England Journal publication is you get the noise of some symptomatic toxicity, some laboratory abnormalities. So, for PD-1 monotherapy, how do you quote to patients’ problematic toxicity? And then, maybe you can frame that also as they may require steroids. What’s that percentage? Because, I think that becomes the kernel of the safety side of efficacy/safety with PD-1 monotherapy that then helps set up the discussion for combination.

Jason J. Luke, MD: Well, I usually quote to patients the incidence of clinically meaningful problematic side effects that’s going to be in the range of 10% to 15%. That’s usually what I quote to patients. And I put that in the context of ipilimumab, where I usually tell them is on the order of 30%. So, that’s a clear improvement. I really spend a fair amount of time emphasizing mechanism of action of these drugs to explain to them why it’s different. This isn’t like a pill that you took that if you just let it wash out it, goes away. But, in fact, this is your own body manifesting an unusual response against itself. I describe that. Then, to go through them serially, to really just force the idea that if something is unusual, you should let us know. Because, sometimes these aren’t as obvious, especially in the monotherapy PD-1. You don’t see much grade 3/4 colitis, but things can happen. And I tell patients the most common is some fatigue. That seems to be very consistent. We see a fair amount of arthralgias, in the Midwest, at least, and I think that that is an area that needs to be explored that we don’t understand mechanistically well, but it’s quite common. And then, we see cutaneous things sometimes, some rashes and so on and so forth. Then, anything beyond that just call us because we need to sort it out further.

Keith T. Flaherty, MD: Jeff, you’ve had a lot of experience with these drugs for a long time. So, what’s the kernel of autoimmune toxicity with PD-1 antibody therapy that really worries you? Patients can have grade 3 rash, and that’s going to be a problematic rash in terms of patients being uncomfortable. But, leaving aside the vast majority of skin toxicities, what are the ones that really make you nervous, make you jump into steroids, and then, what’s that percentage look like in the population you treat?

Jeffrey S. Weber, MD: Well, let’s back up one second. Jason talked about the clinically meaningful toxicities. Usually, when we look at a toxicity table in a publication or on the package insert of a drug, it just gives you a list of how many grade 1/2, how many grade 3/4 toxicities are there. But, I think with these drugs you have to go beyond just the listing or enumeration of the toxicities, and ask two questions. How often do you have to stop the drug and how often do you have to intervene with steroids or other drugs? And, actually, for pembrolizumab and nivolumab, and probably the PD-L1 antibodies also, it’s only about 4% or 5%. That’s the stuff that I think patients really care about. You can certainly have morbidity from severe rashes, but usually if it’s something you don’t have to intervene in, it’s not more than an annoyance. It’s the colitis where you have to intervene; the neuropathies, the nephritis, the hepatitis, and that’s pretty low. For 4% to 5%, it is a very well tolerated drug.

Jason J. Luke, MD: One thing I want to throw when we think of this number, I guess we’re parsing if it’s 5 versus 10, but considering how low that is, I tell people PD-1 antibody is the safest drug we have in all cancer. But, the other big one I didn’t mention is thyroiditis. It’s very, very common that patients will get it. And sometimes it’s asymptomatic, but abnormalities in the thyroid, to a patient learning they have now a thyroid problem, that can be a ‘Oh, wait, why do I have this?’ But, it’s really not a big issue. That’s why I raised it as clinically meaningful.

Jeffrey S. Weber, MD: I would agree.

Jason J. Luke, MD: Because, I think that patients feel that it’s meaningful, they have to start taking levothyroxine or something like that. But, in reality, it’s not dangerous.

Keith T. Flaherty, MD: I agree. Just to second Jeff’s point, I boil it down the same way and I present to patients a 5% number. This is the real kernel of toxicity that is truly problematic. But, then, obviously the transition point here is to PD-1/CTLA4 combination therapy. So, numerically in trials, there were reported grade 3/4 rates of 50% to even 60%, depending on the cohort, but let’s do that again for what’s the kernel of concerning toxicity within the combination, PD-1/CTLA4.

Georgina Long, BSc, MBBS: I have very similar conversations about single agent PD-1. And when it comes to the combination, I take it up a notch. In fact, you can almost guarantee they will develop some toxicity of some kind when you’re combining CTLA4 and anti-PD-1. Colitis is an issue for the patient. It’s the most worrying concern, because I actually get concerned about them sitting on side effects and not reporting it. And this is what I think is really important. I would rather a false alarm than no alarm. So, I tell them the big five, same conversation that Jason has. We’re stimulating your immune system. It’s something that we need to stop with heavy duty drugs if it starts affecting your normal tissue. The big five are your gut with diarrhea, your liver with hepatitis, endocrinopathy—so, your pituitary, and that can be dangerous—thyroid, and skin. And then it can affect almost any other organ, but in much lower percentage. But, if you’re concerned or worried, you must contact and let us know of any little symptom. Let us interpret whether we think it needs more follow up or more intervention, but early intervention is what’s required.

I have to say, I warn them that they will get some sort of side effects. I prime them for that. If they’re one of the lucky few that get through without any side effects, good luck to them. But, the most important thing is managing these toxicities early and quickly. And it is manageable.

Transcript Edited for Clarity

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Transcript:

Keith T. Flaherty, MD:
Let’s switch gears. Thinking about immune checkpoint therapy, we have this historical artifact of ipilimumab being introduced first; PD-1 antibodies being evaluated in ipilimumab refractory patients and associated with response percentages, some of which are in FDA labels. Then, more recently, you get PD-1 inhibitor monotherapy data which, of course, is what we think about when we’re talking to patients about predicted outcome. Jason, you’ve got a patient in front of you—let’s make it easy and say they’re BRAF wild-type—and you’re preparing to have the discussion with the patient about PD-1 monotherapy versus PD-1/CTLA4. But, hold for a moment on that combination part. How do you describe the upsides and downsides of PD-1 antibody monotherapy?

Jason J. Luke, MD: Well, the way I usually describe it to patients is I take them through the historical progression. I actually start from IL-2, and then go to ipilimumab to talk about the progression that we’ve been making with serially increased response rates and durable benefit over time. And when you get to PD-1, you then identify that now you have a 40% response, relative to prior 10%. It looks like there’s a durable amount, at least like maybe in the 30% range, a number of patients are out a long time. And you actually decrease the side effect profile relative to prior immunotherapy approaches. It’s a pretty convincing argument that this is the right thing to do. But, I think there’s really no debate in the field now that in the immunotherapy space, PD-1 antibodies are now the core of immunotherapy in melanoma, and probably more cancers actually. So, I think that that part is very easy. The question then is going on to the combinations, so how you do that?

Keith T. Flaherty, MD: A nice summary on the efficacy side. But, when you’re talking about toxicity, the problem with the discussion if you just go based on lifting data out of a New England Journal publication is you get the noise of some symptomatic toxicity, some laboratory abnormalities. So, for PD-1 monotherapy, how do you quote to patients’ problematic toxicity? And then, maybe you can frame that also as they may require steroids. What’s that percentage? Because, I think that becomes the kernel of the safety side of efficacy/safety with PD-1 monotherapy that then helps set up the discussion for combination.

Jason J. Luke, MD: Well, I usually quote to patients the incidence of clinically meaningful problematic side effects that’s going to be in the range of 10% to 15%. That’s usually what I quote to patients. And I put that in the context of ipilimumab, where I usually tell them is on the order of 30%. So, that’s a clear improvement. I really spend a fair amount of time emphasizing mechanism of action of these drugs to explain to them why it’s different. This isn’t like a pill that you took that if you just let it wash out it, goes away. But, in fact, this is your own body manifesting an unusual response against itself. I describe that. Then, to go through them serially, to really just force the idea that if something is unusual, you should let us know. Because, sometimes these aren’t as obvious, especially in the monotherapy PD-1. You don’t see much grade 3/4 colitis, but things can happen. And I tell patients the most common is some fatigue. That seems to be very consistent. We see a fair amount of arthralgias, in the Midwest, at least, and I think that that is an area that needs to be explored that we don’t understand mechanistically well, but it’s quite common. And then, we see cutaneous things sometimes, some rashes and so on and so forth. Then, anything beyond that just call us because we need to sort it out further.

Keith T. Flaherty, MD: Jeff, you’ve had a lot of experience with these drugs for a long time. So, what’s the kernel of autoimmune toxicity with PD-1 antibody therapy that really worries you? Patients can have grade 3 rash, and that’s going to be a problematic rash in terms of patients being uncomfortable. But, leaving aside the vast majority of skin toxicities, what are the ones that really make you nervous, make you jump into steroids, and then, what’s that percentage look like in the population you treat?

Jeffrey S. Weber, MD: Well, let’s back up one second. Jason talked about the clinically meaningful toxicities. Usually, when we look at a toxicity table in a publication or on the package insert of a drug, it just gives you a list of how many grade 1/2, how many grade 3/4 toxicities are there. But, I think with these drugs you have to go beyond just the listing or enumeration of the toxicities, and ask two questions. How often do you have to stop the drug and how often do you have to intervene with steroids or other drugs? And, actually, for pembrolizumab and nivolumab, and probably the PD-L1 antibodies also, it’s only about 4% or 5%. That’s the stuff that I think patients really care about. You can certainly have morbidity from severe rashes, but usually if it’s something you don’t have to intervene in, it’s not more than an annoyance. It’s the colitis where you have to intervene; the neuropathies, the nephritis, the hepatitis, and that’s pretty low. For 4% to 5%, it is a very well tolerated drug.

Jason J. Luke, MD: One thing I want to throw when we think of this number, I guess we’re parsing if it’s 5 versus 10, but considering how low that is, I tell people PD-1 antibody is the safest drug we have in all cancer. But, the other big one I didn’t mention is thyroiditis. It’s very, very common that patients will get it. And sometimes it’s asymptomatic, but abnormalities in the thyroid, to a patient learning they have now a thyroid problem, that can be a ‘Oh, wait, why do I have this?’ But, it’s really not a big issue. That’s why I raised it as clinically meaningful.

Jeffrey S. Weber, MD: I would agree.

Jason J. Luke, MD: Because, I think that patients feel that it’s meaningful, they have to start taking levothyroxine or something like that. But, in reality, it’s not dangerous.

Keith T. Flaherty, MD: I agree. Just to second Jeff’s point, I boil it down the same way and I present to patients a 5% number. This is the real kernel of toxicity that is truly problematic. But, then, obviously the transition point here is to PD-1/CTLA4 combination therapy. So, numerically in trials, there were reported grade 3/4 rates of 50% to even 60%, depending on the cohort, but let’s do that again for what’s the kernel of concerning toxicity within the combination, PD-1/CTLA4.

Georgina Long, BSc, MBBS: I have very similar conversations about single agent PD-1. And when it comes to the combination, I take it up a notch. In fact, you can almost guarantee they will develop some toxicity of some kind when you’re combining CTLA4 and anti-PD-1. Colitis is an issue for the patient. It’s the most worrying concern, because I actually get concerned about them sitting on side effects and not reporting it. And this is what I think is really important. I would rather a false alarm than no alarm. So, I tell them the big five, same conversation that Jason has. We’re stimulating your immune system. It’s something that we need to stop with heavy duty drugs if it starts affecting your normal tissue. The big five are your gut with diarrhea, your liver with hepatitis, endocrinopathy—so, your pituitary, and that can be dangerous—thyroid, and skin. And then it can affect almost any other organ, but in much lower percentage. But, if you’re concerned or worried, you must contact and let us know of any little symptom. Let us interpret whether we think it needs more follow up or more intervention, but early intervention is what’s required.

I have to say, I warn them that they will get some sort of side effects. I prime them for that. If they’re one of the lucky few that get through without any side effects, good luck to them. But, the most important thing is managing these toxicities early and quickly. And it is manageable.

Transcript Edited for Clarity
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