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Third-Line Treatment for FL: PI3 Kinase Inhibitors

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Jan 23, 2018



Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about third-line therapy. Patients go into remission, you give them R-CHOP to begin with, and then perhaps you use another therapy as a second-line treatment when someone relapses. So, what are our options in third-line therapy?

Anas Younes, MD: That’s a good question. Most of us would start with either BR or R-CHOP, and then if one fails you switch to the other, depending on the duration of initial response. But when both of them fail, what do you do? Now we have 2 FDA-approved agents, and both target PI3 kinase. The first one was idelalisib and the second one was copanlisib, and those would be perfectly suitable for this setup. In countries where these drugs are not available, or if there’s reason not to give either one, most of us used to use R2, lenalidomide plus rituximab. So, I think we have options here. The 2 PI3 kinase inhibitors are good options, and R-squared would also be another good option.

Ian W. Flinn, MD, PhD: How do you figure out whether you need to add Rituxan [rituximab]? I know that in a lot of clinical trials we keep folding in the CD20 antibodies. Not just rituximab, but any of the CD20 antibodies. I’m almost sometimes hesitant not to do that, but there’s not a lot of evidence that you need to. How do you sort that out?

Anas Younes, MD: I agree. I tend to use it without rituximab when I use copanlisib or idelalisib. There are no data that the combination with Rituxan would do better. It may add more toxicities, we don’t know. We need trials to see if the addition of rituximab is required, especially when these drugs were approved for what’s called double refractory disease. Ideally, when these drugs were approved, they were approved for patients who were Rituxan-refractory patients, so it doesn’t make sense to add it. But I’m sure there will be patients who may not be Rituxan refractory. To your question, “Should I add Rituxan?” I don’t tend to do that myself.

Peter Martin, MD, MS: I think that in the context of lenalidomide, for example, even if somebody is rituximab refractory, it may make sense to add rituximab because the mechanism of action of that regimen is that maybe those 2 drugs together are really more synergistic than alone. But I agree that if somebody is rituximab refractory and you’re just adding it on, it’s just adding on toxicity oftentimes.

Ian W. Flinn, MD, PhD: You talked a little bit about the mechanism of action of some of these drugs. What’s the rationale for the PI3 kinase inhibitors? They work differently than cytotoxic chemotherapy. Can you tell us about that?

Peter Martin, MD, MS: That’s a good point in and of itself. If you know that chemotherapy is not working, maybe just doing more of the same thing isn’t the right strategy. And so, looking for novel mechanisms of action is appropriate. PI3 kinase inhibitors, I think, make a lot of sense. I’m not sure that I would have known that before, but when you think of it retrospectively or when you think more about it, we know that follicular lymphoma lives in a microenvironment with a significant dependence on signaling from that microenvironment.

If we can do anything to cut off that signaling, it’s probably a good thing. If you take those lymphoma cells out and you put them in a dish, you can’t keep them alive. If you could do that in a person, that would be a good idea. And so, maybe PI3 kinase inhibitors work in part because they cut off signaling from the microenvironment. I think that’s a rational strategy, and building on that makes sense by potentially combining it with other cell-signaling inhibitors as well.

Ian W. Flinn, MD, PhD: Greg, we know that there are now several different PI3 kinase inhibitors. There are 4 different isoforms of the PI3 kinase inhibitors. Idelalisib is largely a pure delta inhibitor, whereas copanlisib has inhibition of the alpha isoform as well. What does that mean for patients from a side-effect standpoint and ease of use? What are your thoughts on that?

Grzegorz S. Nowakowski, MD: It’s very interesting because there is some preclinical evidence that some of the resistance to PI3 kinase inhibitors could be mediated through the alpha isoform. There is a strong rationale for inhibiting both alpha and delta isoform in the tumors in lymphoma, and solid tumors as well. But alpha isoform is involved in a metabolic process antibody, which is related to very unusual and specific toxicities of alpha isoform inhibitors. So, in the case of copanlisib, you actually see increase in the blood pressure, which is usually transient from an infusion, but it’s common in patients.

And the other thing that you see is hyperglycemia, again through the same mechanism of insulin resistance. Those are side effects that are common, but they are very manageable with appropriate therapy, and there are specific guidelines that are developed and should be observed for the duration of observation after infusion. So, it’s manageable, but inhibition of the alpha subunit does result in a different toxicity profile. It is interesting if this inhibition of the alpha subunit will result in better tumor control, if indeed we will see some of the emergence of the resistance could be related to lack of inhibition of alpha subunit.

Ian W. Flinn, MD, PhD: Could the inhibition of the alpha isoform also improve tolerability in terms of perhaps the diarrhea that is sometimes seen with idelalisib? We know from the knockout mice or knock-in mice models that deletion of the delta isoform led to this colitis. It’s not seen as much with copanlisib as it was with idelalisib. What’s your take on that?

Grzegorz S. Nowakowski, MD: You’re absolutely right. It’s not very common with copanlisib, which is actually a major advantage of this drug. The mechanism could be inhibition of alpha subunit, but it also could be the route of administration. It is an IV formulation, so maybe the exposure to the GI tract is actually different for the drug, which may result in this different toxicity profile. It could also be related to certain metabolites and how it’s being metabolized in the body. We know, for example, that liver toxicity is also very unusual with copanlisib, which is good to see because it offers more option for our patients.

Anas Younes, MD: I doubt alpha is the one that is interfering with the colitis. I think it’s delta. But I think I agree with you about the route of administration. We have a high peak and it clears quickly, so you don’t have constant exposure to PI3 kinase inhibitors throughout the week. Whereas, when you give it orally for some of these agents, you’re constantly inhibiting delta and that’s probably what’s causing it.

Ian W. Flinn, MD, PhD: Is that enough to make you want to use an IV formulation over an oral formulation? There are clearly patients who would prefer to have oral administration, and maybe there are some who would prefer to have an IV.

Anas Younes, MD: It depends on the drug. For now, between these 2 commercially available options, I think it happened that copanlisib has a better safety profile. It happens to be IV. I don’t think the IV form per se is the reason. I’m sure we should probably at one point find an orally administered agent that also could be safe. So, there are early indications that some PI3 kinase inhibitors in clinical trials are also getting good, early safety signals. Of course, long-term follow-up would be the important thing to find out if this is a true signal or not.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about third-line therapy. Patients go into remission, you give them R-CHOP to begin with, and then perhaps you use another therapy as a second-line treatment when someone relapses. So, what are our options in third-line therapy?

Anas Younes, MD: That’s a good question. Most of us would start with either BR or R-CHOP, and then if one fails you switch to the other, depending on the duration of initial response. But when both of them fail, what do you do? Now we have 2 FDA-approved agents, and both target PI3 kinase. The first one was idelalisib and the second one was copanlisib, and those would be perfectly suitable for this setup. In countries where these drugs are not available, or if there’s reason not to give either one, most of us used to use R2, lenalidomide plus rituximab. So, I think we have options here. The 2 PI3 kinase inhibitors are good options, and R-squared would also be another good option.

Ian W. Flinn, MD, PhD: How do you figure out whether you need to add Rituxan [rituximab]? I know that in a lot of clinical trials we keep folding in the CD20 antibodies. Not just rituximab, but any of the CD20 antibodies. I’m almost sometimes hesitant not to do that, but there’s not a lot of evidence that you need to. How do you sort that out?

Anas Younes, MD: I agree. I tend to use it without rituximab when I use copanlisib or idelalisib. There are no data that the combination with Rituxan would do better. It may add more toxicities, we don’t know. We need trials to see if the addition of rituximab is required, especially when these drugs were approved for what’s called double refractory disease. Ideally, when these drugs were approved, they were approved for patients who were Rituxan-refractory patients, so it doesn’t make sense to add it. But I’m sure there will be patients who may not be Rituxan refractory. To your question, “Should I add Rituxan?” I don’t tend to do that myself.

Peter Martin, MD, MS: I think that in the context of lenalidomide, for example, even if somebody is rituximab refractory, it may make sense to add rituximab because the mechanism of action of that regimen is that maybe those 2 drugs together are really more synergistic than alone. But I agree that if somebody is rituximab refractory and you’re just adding it on, it’s just adding on toxicity oftentimes.

Ian W. Flinn, MD, PhD: You talked a little bit about the mechanism of action of some of these drugs. What’s the rationale for the PI3 kinase inhibitors? They work differently than cytotoxic chemotherapy. Can you tell us about that?

Peter Martin, MD, MS: That’s a good point in and of itself. If you know that chemotherapy is not working, maybe just doing more of the same thing isn’t the right strategy. And so, looking for novel mechanisms of action is appropriate. PI3 kinase inhibitors, I think, make a lot of sense. I’m not sure that I would have known that before, but when you think of it retrospectively or when you think more about it, we know that follicular lymphoma lives in a microenvironment with a significant dependence on signaling from that microenvironment.

If we can do anything to cut off that signaling, it’s probably a good thing. If you take those lymphoma cells out and you put them in a dish, you can’t keep them alive. If you could do that in a person, that would be a good idea. And so, maybe PI3 kinase inhibitors work in part because they cut off signaling from the microenvironment. I think that’s a rational strategy, and building on that makes sense by potentially combining it with other cell-signaling inhibitors as well.

Ian W. Flinn, MD, PhD: Greg, we know that there are now several different PI3 kinase inhibitors. There are 4 different isoforms of the PI3 kinase inhibitors. Idelalisib is largely a pure delta inhibitor, whereas copanlisib has inhibition of the alpha isoform as well. What does that mean for patients from a side-effect standpoint and ease of use? What are your thoughts on that?

Grzegorz S. Nowakowski, MD: It’s very interesting because there is some preclinical evidence that some of the resistance to PI3 kinase inhibitors could be mediated through the alpha isoform. There is a strong rationale for inhibiting both alpha and delta isoform in the tumors in lymphoma, and solid tumors as well. But alpha isoform is involved in a metabolic process antibody, which is related to very unusual and specific toxicities of alpha isoform inhibitors. So, in the case of copanlisib, you actually see increase in the blood pressure, which is usually transient from an infusion, but it’s common in patients.

And the other thing that you see is hyperglycemia, again through the same mechanism of insulin resistance. Those are side effects that are common, but they are very manageable with appropriate therapy, and there are specific guidelines that are developed and should be observed for the duration of observation after infusion. So, it’s manageable, but inhibition of the alpha subunit does result in a different toxicity profile. It is interesting if this inhibition of the alpha subunit will result in better tumor control, if indeed we will see some of the emergence of the resistance could be related to lack of inhibition of alpha subunit.

Ian W. Flinn, MD, PhD: Could the inhibition of the alpha isoform also improve tolerability in terms of perhaps the diarrhea that is sometimes seen with idelalisib? We know from the knockout mice or knock-in mice models that deletion of the delta isoform led to this colitis. It’s not seen as much with copanlisib as it was with idelalisib. What’s your take on that?

Grzegorz S. Nowakowski, MD: You’re absolutely right. It’s not very common with copanlisib, which is actually a major advantage of this drug. The mechanism could be inhibition of alpha subunit, but it also could be the route of administration. It is an IV formulation, so maybe the exposure to the GI tract is actually different for the drug, which may result in this different toxicity profile. It could also be related to certain metabolites and how it’s being metabolized in the body. We know, for example, that liver toxicity is also very unusual with copanlisib, which is good to see because it offers more option for our patients.

Anas Younes, MD: I doubt alpha is the one that is interfering with the colitis. I think it’s delta. But I think I agree with you about the route of administration. We have a high peak and it clears quickly, so you don’t have constant exposure to PI3 kinase inhibitors throughout the week. Whereas, when you give it orally for some of these agents, you’re constantly inhibiting delta and that’s probably what’s causing it.

Ian W. Flinn, MD, PhD: Is that enough to make you want to use an IV formulation over an oral formulation? There are clearly patients who would prefer to have oral administration, and maybe there are some who would prefer to have an IV.

Anas Younes, MD: It depends on the drug. For now, between these 2 commercially available options, I think it happened that copanlisib has a better safety profile. It happens to be IV. I don’t think the IV form per se is the reason. I’m sure we should probably at one point find an orally administered agent that also could be safe. So, there are early indications that some PI3 kinase inhibitors in clinical trials are also getting good, early safety signals. Of course, long-term follow-up would be the important thing to find out if this is a true signal or not.

Transcript Edited for Clarity 
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