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PI3 Kinase Inhibitors for Third-Line Therapy in FL

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew Lunning, DO, University of Nebraska Medical Center; John M. Pagel, MD, PhD, Swedish Cancer Institute; Pier Luigi Zinzani, MD, PhD, University of Bologna
Published: Wednesday, Aug 28, 2019



Transcript: 

Ian W. Flinn, MD, PhD: We’re going to make it even more complicated. We’re going to move down the line. We’re going to talk about third-line setting. John, talk a little about the rationale for—we now have several different PI3 kinase inhibitors. Why use a PI3 kinase inhibitor in patients with follicular lymphoma?

John M. Pagel, MD, PhD: Well, I think there are a couple of things to remember. One is that the drugs have reasonably good activity in relapsed follicular lymphoma. Response rates are on the order of 50% or so. They can have remissions that can last perhaps quite durably, but particularly median durations of remission are on the order of a year or perhaps even a little less. But the idea of using these agents is in someone in whom you may think more chemotherapy or standard regimens are not going to give as much benefit as you like, and you’re really looking for a different mechanism of action of cell killing. A targeted agent that’s, well, not necessarily cytotoxic chemotherapy might make sense. It’s a different way to kill these cells. It may get around a little bit of resistance you might have seen if in fact there is such a thing as resistance—in the POD 24 [progression of disease in 24 months] patients, as an example. And I think that rationale has scientific basis to it.

I think the big problem we have is not knowing which of these agents to use, and that’s something I’m sure we’ll talk about as well. But you mentioned that there are several agents. And I think what’s most important to say is that this class of drugs, in my opinion, should not be forgotten in this disease. This is something that really can help patients. I have had patients on a PI3 kinase inhibitor with relapsed follicular lymphoma who have had really quite striking reversal turnaround of their disease and done extremely well for a long period of time. It’s a class of drugs that we need to remember that’s in our tool chest, in our back pocket.

Ian W. Flinn, MD, PhD: Yeah. And we just saw last fall the approval of duvelisib for patients with 2 prior therapies with follicular lymphoma. This is based on the DYNAMO trial. The DYNAMO trial was a single-arm phase II trial with more than 120 patients with all low-grade lymphomas that were entered into the study. They had to be double refractory, right? These patients, they had to be refractory to both rituximab and chemoimmunotherapy. And so in this study we saw a 47% overall response rate and substantial progression-free survival and duration of response. It was from this study that duvelisib received its label. And the label is not exactly the patients who were on the trial. It’s for 2 prior therapy patients, not just the double refractory, which I think is helpful in everyday practice. Pier Luigi, you were part of this study as well. Can you talk to us a little about some of the prognostic factors? I think you had a paper on some of the immunologic factors that might predict? Is that something we can use every day in practice, or is it mostly just interesting?

Pier Luigi Zinzani, MD, PhD: Unfortunately, it’s so difficult. We need a retrospective evaluation of several chemokines and cytokines to stratify the patient according to the responder versus no responder. But so far it is too difficult to apply this kind of a biological evaluation in the clinical practice. Could be in the future but we need more patients, longer follow-up to really understand if there are some biopathological factors that you can stratify the responder versus the nonresponder patients.

Ian W. Flinn, MD, PhD: You know all PI3 kinase inhibitors are not the same. We think about idelalisib being a delta inhibitor. Duvelisib is an inhibitor both at delta and gamma isoforms. There is a notion that it may be hard to demonstrate clinically because of just the issues, the difficulty of studying this, but that by inhibiting the microenvironment we might increase the activity of duvelisib. There are some data that it helps in T-cell lymphomas as well. Have you used duvelisib, and what’s your experience, Matt, with this drug?

Matthew Lunning, DO: I’ve started to use it. I think it’s an oral twice-a-day drug, so on-label use. I’ve seen people tolerate it. I just have to get more months on the drug before you can; I think part of this class is being able to tolerate it not only for the first 3 months, but it’s got to be a drug that you’re expecting. If there are patients are in remission, it has to be able to take for a long period of time. I think that 1 of the things going through the class is, do you need it all the time? Do you need to inhibit PI3 kinase all the time? Whichever isoform you’re inhibiting, is it good? Or is it good to give a drug holiday or intermittent dosing? I think those are the things that are coming back around in the class.

Ian W. Flinn, MD, PhD: Yeah, it’s unfortunate that sometimes, just to get these drugs approved, we have some very straightforward things. But we have a lot to learn with duvelisib; we have a lot to learn with all these inhibitors. We’re going to talk a little later about some of the newer agents. And the question will come up, just as you’re saying, is it the drug that’s different or is it the schedule that it’s being used in? And is that better timing?

We know, of course, that all these classes of agents have adverse events, such as immune-related events, that are concerning. But is this drug different—in terms of the isoforms it hits—from copanlisib?

John M. Pagel, MD, PhD: Right. Well, I think that’s the interesting thing about duvelisib that does make it at least scientifically exciting, that it also hits the gamma isoform in addition to the delta isoform. So if you remember, idelalisib is really a pure delta inhibitor. And of course, as we’ve said, duvelisib hits gamma as well, and that’s the idea that maybe it’s causing some changes in the tumor microenvironment that would be important for inhibiting cell growth or proliferation, so it’s through interactions with myeloid cells or even T cells in the microenvironment. I think that data are very appealing from a scientific standpoint. From a clinical translation, I’m not sure they necessarily make a difference that we’ve seen, but we’ll know even more when we start looking at the results from the T-cell studies that you alluded to.

Copanlisib is a little different, and you mentioned that. That’s an IV [intravenous] formulation of a PI3 kinase inhibitor, whereas duvelisib and idelalisib are oral agents. The copanlisib, I think, has been limited in its use and exposure in the United States simply because of that IV administration that’s weekly for 3 weeks out of 4, and you’re doing that essentially indefinitely. There are a lot of trips to the clinic; that’s a lot of infusion time in the treatment center. Eventually there’s fatigue with that from a patient standpoint. That’s a little different drug, and maybe in fact that’s another drug for which we say, “You know, we might take a bit of a holiday.” I would say we’ve got to learn more about all these agents.

Ian W. Flinn, MD, PhD: The schedule of the administration is very different. You’re getting this intermittent scheduling and intermittent dosing, which perhaps improves the adverse-event profile with copanlisib. Duvelisib is a continuous oral dose, but perhaps I know that the duvelisib investigators are looking at alternative scheduling, such as what you’ve mentioned with holidays, decreased dosing, induction, and things like that.

Matthew Lunning, DO: I think there are also some interesting clinical trials going on with duvelisib. I think the 1 that I’ve been watching the most is the duvelisib romidepsin study. While it’s in a single center, the data have now presented multiple times kind of as the study kind of grows. They’re giving a very interesting toxicity profile. What is romidepsin doing in a kind of epigenetic fashion that may lessen toxicities or dampen that? We’re getting potentially some efficacy in T-cell lymphomas, but also I think there were some B-cell patients on that study.

Ian W. Flinn, MD, PhD: The initial hypothesis, Pier Luigi, with idelalisib was that by hitting the specific isoform, the delta isoform, you would not get the off-target toxicity or the toxicity associated with hitting the other isoforms. Of course, there’s also another potential corollary to that: by hitting only the delta isoform, you’re going to open yourself up to some of the immunologic toxicities that were predicted in a mouse model prior to that.

In copanlisib, you’re hitting both the alpha isoform and the delta isoform. And it’s a different schedule; it’s IV. There are a whole bunch of differences. But maybe those are the same things we’re seeing with the romidepsin-type data, in which you have a combination of drugs. Usually when you combine 2 drugs you get worse toxicity. In this case you’re actually getting better toxicity when you add it to duvelisib.

Pier Luigi Zinzani, MD, PhD: I was involved with the CHRONOS-1 study with copanlisib….With copy you can use the toxicity in term of immune-mediated toxicity like colitis, pneumonitis, transaminitis, but there is an increase of hyperglycemia and hypertension that could be easier to manage.

At the same time the difference in terms of toxicity could be related also the schedule, because it’s intravenous but it’s day 1, 8, and 15—every 4 weeks. So it’s a weekly administration. It’s a different situation when you compare with daily treatment for idela [idelalisib] or for duvelisib, and this could be quite important in terms of the real toxicity when you compare copa [copanlisib] versus the other inhibitors, like duvelisib and idelalisib.

Logistically it’s quite difficult to use copanlisib because most of the patients are older patients who need to go to the clinic every couple of weeks for the intravenous administration. So it’s a balance. It is a real specific toxicity related…to the increase of hyperglycemia and hypertension.

Ian W. Flinn, MD, PhD: What do you think about the alpha isoform? We know there are data at least in mantle cell lymphoma that may be important, in similar events in mantle cell lymphoma. I don’t think we have the same data in follicular lymphoma even in chronic lymphocytic leukemia.  What are your thoughts on that?

Pier Luigi Zinzani, MD, PhD: Yeah. This is very interesting for this reason the status of a few trials concerning the potential combination of copanlisib plus ibrutinib in the treatment of relapsed and refractory mantle cell lymphoma. So there’s a good preclinical rationale to do that, according to this alpha isoform, to try to combine and use this drug in the treatment of mantle cell lymphoma.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: We’re going to make it even more complicated. We’re going to move down the line. We’re going to talk about third-line setting. John, talk a little about the rationale for—we now have several different PI3 kinase inhibitors. Why use a PI3 kinase inhibitor in patients with follicular lymphoma?

John M. Pagel, MD, PhD: Well, I think there are a couple of things to remember. One is that the drugs have reasonably good activity in relapsed follicular lymphoma. Response rates are on the order of 50% or so. They can have remissions that can last perhaps quite durably, but particularly median durations of remission are on the order of a year or perhaps even a little less. But the idea of using these agents is in someone in whom you may think more chemotherapy or standard regimens are not going to give as much benefit as you like, and you’re really looking for a different mechanism of action of cell killing. A targeted agent that’s, well, not necessarily cytotoxic chemotherapy might make sense. It’s a different way to kill these cells. It may get around a little bit of resistance you might have seen if in fact there is such a thing as resistance—in the POD 24 [progression of disease in 24 months] patients, as an example. And I think that rationale has scientific basis to it.

I think the big problem we have is not knowing which of these agents to use, and that’s something I’m sure we’ll talk about as well. But you mentioned that there are several agents. And I think what’s most important to say is that this class of drugs, in my opinion, should not be forgotten in this disease. This is something that really can help patients. I have had patients on a PI3 kinase inhibitor with relapsed follicular lymphoma who have had really quite striking reversal turnaround of their disease and done extremely well for a long period of time. It’s a class of drugs that we need to remember that’s in our tool chest, in our back pocket.

Ian W. Flinn, MD, PhD: Yeah. And we just saw last fall the approval of duvelisib for patients with 2 prior therapies with follicular lymphoma. This is based on the DYNAMO trial. The DYNAMO trial was a single-arm phase II trial with more than 120 patients with all low-grade lymphomas that were entered into the study. They had to be double refractory, right? These patients, they had to be refractory to both rituximab and chemoimmunotherapy. And so in this study we saw a 47% overall response rate and substantial progression-free survival and duration of response. It was from this study that duvelisib received its label. And the label is not exactly the patients who were on the trial. It’s for 2 prior therapy patients, not just the double refractory, which I think is helpful in everyday practice. Pier Luigi, you were part of this study as well. Can you talk to us a little about some of the prognostic factors? I think you had a paper on some of the immunologic factors that might predict? Is that something we can use every day in practice, or is it mostly just interesting?

Pier Luigi Zinzani, MD, PhD: Unfortunately, it’s so difficult. We need a retrospective evaluation of several chemokines and cytokines to stratify the patient according to the responder versus no responder. But so far it is too difficult to apply this kind of a biological evaluation in the clinical practice. Could be in the future but we need more patients, longer follow-up to really understand if there are some biopathological factors that you can stratify the responder versus the nonresponder patients.

Ian W. Flinn, MD, PhD: You know all PI3 kinase inhibitors are not the same. We think about idelalisib being a delta inhibitor. Duvelisib is an inhibitor both at delta and gamma isoforms. There is a notion that it may be hard to demonstrate clinically because of just the issues, the difficulty of studying this, but that by inhibiting the microenvironment we might increase the activity of duvelisib. There are some data that it helps in T-cell lymphomas as well. Have you used duvelisib, and what’s your experience, Matt, with this drug?

Matthew Lunning, DO: I’ve started to use it. I think it’s an oral twice-a-day drug, so on-label use. I’ve seen people tolerate it. I just have to get more months on the drug before you can; I think part of this class is being able to tolerate it not only for the first 3 months, but it’s got to be a drug that you’re expecting. If there are patients are in remission, it has to be able to take for a long period of time. I think that 1 of the things going through the class is, do you need it all the time? Do you need to inhibit PI3 kinase all the time? Whichever isoform you’re inhibiting, is it good? Or is it good to give a drug holiday or intermittent dosing? I think those are the things that are coming back around in the class.

Ian W. Flinn, MD, PhD: Yeah, it’s unfortunate that sometimes, just to get these drugs approved, we have some very straightforward things. But we have a lot to learn with duvelisib; we have a lot to learn with all these inhibitors. We’re going to talk a little later about some of the newer agents. And the question will come up, just as you’re saying, is it the drug that’s different or is it the schedule that it’s being used in? And is that better timing?

We know, of course, that all these classes of agents have adverse events, such as immune-related events, that are concerning. But is this drug different—in terms of the isoforms it hits—from copanlisib?

John M. Pagel, MD, PhD: Right. Well, I think that’s the interesting thing about duvelisib that does make it at least scientifically exciting, that it also hits the gamma isoform in addition to the delta isoform. So if you remember, idelalisib is really a pure delta inhibitor. And of course, as we’ve said, duvelisib hits gamma as well, and that’s the idea that maybe it’s causing some changes in the tumor microenvironment that would be important for inhibiting cell growth or proliferation, so it’s through interactions with myeloid cells or even T cells in the microenvironment. I think that data are very appealing from a scientific standpoint. From a clinical translation, I’m not sure they necessarily make a difference that we’ve seen, but we’ll know even more when we start looking at the results from the T-cell studies that you alluded to.

Copanlisib is a little different, and you mentioned that. That’s an IV [intravenous] formulation of a PI3 kinase inhibitor, whereas duvelisib and idelalisib are oral agents. The copanlisib, I think, has been limited in its use and exposure in the United States simply because of that IV administration that’s weekly for 3 weeks out of 4, and you’re doing that essentially indefinitely. There are a lot of trips to the clinic; that’s a lot of infusion time in the treatment center. Eventually there’s fatigue with that from a patient standpoint. That’s a little different drug, and maybe in fact that’s another drug for which we say, “You know, we might take a bit of a holiday.” I would say we’ve got to learn more about all these agents.

Ian W. Flinn, MD, PhD: The schedule of the administration is very different. You’re getting this intermittent scheduling and intermittent dosing, which perhaps improves the adverse-event profile with copanlisib. Duvelisib is a continuous oral dose, but perhaps I know that the duvelisib investigators are looking at alternative scheduling, such as what you’ve mentioned with holidays, decreased dosing, induction, and things like that.

Matthew Lunning, DO: I think there are also some interesting clinical trials going on with duvelisib. I think the 1 that I’ve been watching the most is the duvelisib romidepsin study. While it’s in a single center, the data have now presented multiple times kind of as the study kind of grows. They’re giving a very interesting toxicity profile. What is romidepsin doing in a kind of epigenetic fashion that may lessen toxicities or dampen that? We’re getting potentially some efficacy in T-cell lymphomas, but also I think there were some B-cell patients on that study.

Ian W. Flinn, MD, PhD: The initial hypothesis, Pier Luigi, with idelalisib was that by hitting the specific isoform, the delta isoform, you would not get the off-target toxicity or the toxicity associated with hitting the other isoforms. Of course, there’s also another potential corollary to that: by hitting only the delta isoform, you’re going to open yourself up to some of the immunologic toxicities that were predicted in a mouse model prior to that.

In copanlisib, you’re hitting both the alpha isoform and the delta isoform. And it’s a different schedule; it’s IV. There are a whole bunch of differences. But maybe those are the same things we’re seeing with the romidepsin-type data, in which you have a combination of drugs. Usually when you combine 2 drugs you get worse toxicity. In this case you’re actually getting better toxicity when you add it to duvelisib.

Pier Luigi Zinzani, MD, PhD: I was involved with the CHRONOS-1 study with copanlisib….With copy you can use the toxicity in term of immune-mediated toxicity like colitis, pneumonitis, transaminitis, but there is an increase of hyperglycemia and hypertension that could be easier to manage.

At the same time the difference in terms of toxicity could be related also the schedule, because it’s intravenous but it’s day 1, 8, and 15—every 4 weeks. So it’s a weekly administration. It’s a different situation when you compare with daily treatment for idela [idelalisib] or for duvelisib, and this could be quite important in terms of the real toxicity when you compare copa [copanlisib] versus the other inhibitors, like duvelisib and idelalisib.

Logistically it’s quite difficult to use copanlisib because most of the patients are older patients who need to go to the clinic every couple of weeks for the intravenous administration. So it’s a balance. It is a real specific toxicity related…to the increase of hyperglycemia and hypertension.

Ian W. Flinn, MD, PhD: What do you think about the alpha isoform? We know there are data at least in mantle cell lymphoma that may be important, in similar events in mantle cell lymphoma. I don’t think we have the same data in follicular lymphoma even in chronic lymphocytic leukemia.  What are your thoughts on that?

Pier Luigi Zinzani, MD, PhD: Yeah. This is very interesting for this reason the status of a few trials concerning the potential combination of copanlisib plus ibrutinib in the treatment of relapsed and refractory mantle cell lymphoma. So there’s a good preclinical rationale to do that, according to this alpha isoform, to try to combine and use this drug in the treatment of mantle cell lymphoma.

Transcript Edited for Clarity
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