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Future of PI3K Inhibition in FL and CLL

Insights From: Ian Flinn, MD, PhD, Sarah Cannon Research Institute
Published: Friday, Sep 13, 2019



Transcript: 

Ian Flinn, MD, PhD: In follicular lymphoma, the choice of which PI3-kinase inhibitor to use is largely driven based on a few fundamental issues. One, are you looking for an IV [intravenous] formulation, or are you looking for an oral formulation? The IV would push you obviously toward copanlisib, or either duvelisib or idelalisib. With regard to some of the other comorbidities, if someone was a diabetic or had problems with hypertension, you’d probably want to stay away from copanlisib and use 1 of the oral inhibitors. We do not have comparative trials between duvelisib and idelalisib to definitively say which 1 is better in terms of some of the adverse-event profiles. Although if you look at the package inserts, there are some differences in terms of that and that might lend you to use 1 over another.

I think 1 of the most important issues for PI3-kinase inhibitors is trying to manage the adverse-event profile. We know that these drugs have tremendous efficacy, but they also come with some baggage, though of some adverse events—some of the infectious complications, some of the autoimmune complications such as colitis and liver function abnormalities. Trying to find ways that improve the safety profile is paramount. We know that in some studies that dose reduction has led to patients staying on drugs for longer. For my own patient population, I know that when I’ve had to dose-reduce patients, I’ve been able sometimes to keep people on a drug for many years at that reduced dose. So I don’t try to dose escalate for the vast majority of patients, because they seem to have the same efficacy.

But you have to wonder whether a different schedule is important. We know what giving continuous PI3-kinase inhibition does, but perhaps we should be using alternative schedules, such as every other week or 2 weeks on, 2 weeks off. Maybe it should be an induction dose followed by a reduced dose afterward. Maybe this would allow us to use these inhibitors more broadly.

If we know that if we’re going to get the most out of these PI3-kinase inhibitors, we have to be able to use them earlier in the natural history of this disease. Finding strategies that allow us to use them earlier, such as those just outlined, are really important.

I think there are also a number of questions that are unanswered with PI3-kinase inhibitors. They’re approved now for the treatment of low-grade lymphoma, and they’re approved for the treatment of chronic lymphocytic leukemia. But some of these PI3-kinase inhibitors might be useful in other malignancies. For instance, we know with duvelisib, there are good data in T-cell malignancies that might broaden its applications. You could wonder whether they also might be useful in diseases such as mantle cell lymphoma—and specifically whether inhibiting the alpha isoform, such as copanlisib, might be useful there. There are many different questions that need to be answered, not only making these regimens more tolerable but on using these regimens in other malignancies to broaden their application.

Transcript Edited for Clarity
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Transcript: 

Ian Flinn, MD, PhD: In follicular lymphoma, the choice of which PI3-kinase inhibitor to use is largely driven based on a few fundamental issues. One, are you looking for an IV [intravenous] formulation, or are you looking for an oral formulation? The IV would push you obviously toward copanlisib, or either duvelisib or idelalisib. With regard to some of the other comorbidities, if someone was a diabetic or had problems with hypertension, you’d probably want to stay away from copanlisib and use 1 of the oral inhibitors. We do not have comparative trials between duvelisib and idelalisib to definitively say which 1 is better in terms of some of the adverse-event profiles. Although if you look at the package inserts, there are some differences in terms of that and that might lend you to use 1 over another.

I think 1 of the most important issues for PI3-kinase inhibitors is trying to manage the adverse-event profile. We know that these drugs have tremendous efficacy, but they also come with some baggage, though of some adverse events—some of the infectious complications, some of the autoimmune complications such as colitis and liver function abnormalities. Trying to find ways that improve the safety profile is paramount. We know that in some studies that dose reduction has led to patients staying on drugs for longer. For my own patient population, I know that when I’ve had to dose-reduce patients, I’ve been able sometimes to keep people on a drug for many years at that reduced dose. So I don’t try to dose escalate for the vast majority of patients, because they seem to have the same efficacy.

But you have to wonder whether a different schedule is important. We know what giving continuous PI3-kinase inhibition does, but perhaps we should be using alternative schedules, such as every other week or 2 weeks on, 2 weeks off. Maybe it should be an induction dose followed by a reduced dose afterward. Maybe this would allow us to use these inhibitors more broadly.

If we know that if we’re going to get the most out of these PI3-kinase inhibitors, we have to be able to use them earlier in the natural history of this disease. Finding strategies that allow us to use them earlier, such as those just outlined, are really important.

I think there are also a number of questions that are unanswered with PI3-kinase inhibitors. They’re approved now for the treatment of low-grade lymphoma, and they’re approved for the treatment of chronic lymphocytic leukemia. But some of these PI3-kinase inhibitors might be useful in other malignancies. For instance, we know with duvelisib, there are good data in T-cell malignancies that might broaden its applications. You could wonder whether they also might be useful in diseases such as mantle cell lymphoma—and specifically whether inhibiting the alpha isoform, such as copanlisib, might be useful there. There are many different questions that need to be answered, not only making these regimens more tolerable but on using these regimens in other malignancies to broaden their application.

Transcript Edited for Clarity
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