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PI3K-Targeted Therapy for R/R Follicular Lymphoma

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Joshua Brody, MD, Icahn School of Medicine at Mount Sanai; Nathan H. Fowler, MD, University of Texas MD Anderson Cancer Center; John P. Leonard, MD, New York Presbyterian/Weill Cornell Medical Center; Matthew Lunning, DO, University of Nebraska Medical Center; Sonali M. Smith, MD, University of Chicago
Published: Wednesday, Aug 15, 2018



Transcript: 

Ian W. Flinn, MD, PhD: John mentioned the PI3-kinase inhibitors, and perhaps 1 of the appeals of this is that they have a different mechanism of action. They’re not the cytotoxic chemotherapy that we’ve been using. Matt, can you explain that a little bit?

Matthew Lunning, DO: It’s been an interesting story to watch the landscape of the PI3-kinase class take shape, starting with the delta inhibitors, and then you have the delta-gamma inhibitors, and now you have delta-alpha inhibitors. These isoforms—at least the delta-specific isoforms—were felt to be the pathway that was involved in the B-cell pathway in lymphomagenesis, regarding…the contribution that the alpha isoform brings potentially to drug resistance, but also looking at bringing in the gamma and where that may play in certain types of lymphomas. So, I think when you have now 3 agents that you’re looking at with approvals in the follicular lymphoma space and how you’re going to use them moving forward, it will be interesting to slice and dice those drugs.

Ian W. Flinn, MD, PhD: There are these 4 different isoforms. I remember originally, when we were working on idelalisib, the concern was that by using 1 isoform-specific inhibitor…you would get mechanisms of escape through some of the other isoforms. I think there are some data, at least in Mantle cell lymphoma, that that’s a real possibility. It is less clear to me in some of the others; at least it’s hard to prove one way or the other. Now there are 2 FDA-approved PI3-kinase inhibitors for follicular lymphoma, both idelalisib and copanlisib; they are different. What do you think of these? Do you think it makes a difference? One is a pure delta inhibitor; one also inhibits the alpha isoform. What are your thoughts?

Sonali M. Smith, MD: Idelalisib, as you said, is the first one that was approved and that hits delta specifically. It’s an oral agent that is approved for relapsed and refractory disease. The study that really showed its efficacy was a really strong study in terms of looking at probably the highest-risk people with follicular lymphoma; this double-refractory group of people that have refractory disease to both alkylating agents and rituximab. There you see a really nice activity and efficacy profile, but the challenge, as we’ve learned over time, is that there is also a unique toxicity profile of transaminase elevation, and some colitis that can be very severe, and pneumonitis, and there’s also infection. As an oral agent, it’s appealing, but there are these toxicities that have to be considered.

Copanlisib came along; I think there are 2 important differences from idelalisib. One is that it also targets the alpha isoforms; you get alpha and delta inhibition. The second major difference is that it’s given intravenously, and the schedule is an hour once a week for 3 weeks out of 4. So, it’s a little more of an injection burden for patients, but in terms of the CHRONOS study that you just referred to, it shows that the response rate is somewhere close to 60%. Complete response rate is low; it’s probably in the 13% to 15% rate, but it has a very different toxicity profile.

You don’t see the same transaminase elevation, but what you do see are more of the alpha effects. You see hypertension and hyperglycemia that are very transient, and I think for people who are not expecting it, it can be probably pretty shocking, because the hyperglycemia occurs very quickly after the infusion and can be quite high but then also rapidly drops. The same thing with the hypertension; you can have grade 2 or more hypertension, but again, it drops, and most people tend to be asymptomatic. Using copanlisib just needs some awareness of what toxicity to look for. All of that being said, I think the toxicity profile is favorable. These are transient effects, and I think whether or not you use one or the other probably is going to have more to do with reimbursement and patient selection, in terms of an oral versus intravenous, than anything.

Ian W. Flinn, MD, PhD: They do have very different profiles and 1 adverse event profile, so I guess 1 explanation is that it’s the different isoforms operating, right? We’re hitting delta versus delta and alpha. Other people have argued, and some of the authors on the copanlisib study had argued, that it was the schedule and not constantly hitting it. John, you’ve done a lot of work with PI3-kinase inhibitors. What’s your take on that? I’m not so sure that with any of the drugs we’re giving, we know the right dose and schedule. Maybe we should be exploring some of these other schedules with some of the drugs that we already have.

John P. Leonard, MD: Yes, I think it’s a fair point. At the end of the day, we don’t have a great sense of whether or not changing the schedule or changing the exposure to the drug will ameliorate toxicities certainly. But, from the standpoint of compromising efficacy, we don’t know. With the toxicities for both of the PI3-kinase inhibitors that are approved, the good part is that we know, and we were a little surprised with idelalisib with what occurred as far as toxicity. Now we know what can happen, and if we’re monitoring patients, the expectations are different. With copanlisib, there are some pretty well-established monitoring guidelines and some predictability as to when you have to worry about the toxicities and then when you get beyond them. In my mind, these are particularly useful drugs for older patients, and we have a lot of follicular lymphoma patients that are older. When they’ve been through a couple of different chemotherapy regimens, they’re not excited to have them; they’re not headed toward transplant. You can get good mileage, and again, with care and with monitoring, can manage the toxicities reasonably well.

Ian W. Flinn, MD, PhD: We should also talk a little bit about duvelisib. Duvelisib is a PI3-kinase, delta and gamma isoform-specific inhibitor, so it doesn’t really pick up much in the way of alpha. That’s currently in development. This is a drug that has been studied in a variety of hematological diseases, including low-grade lymphoma. In the DYNAMO study, we saw about a 50% overall response rate in that very difficult patient population that you talked about earlier, where it was the patients that were double refractory; refractory to both rituximab and to chemotherapy. I thought those were pretty exciting data. That’s before the FDA, so by October, we should know whether that one gets approved. It does have some similar toxicities that we see, perhaps with idelalisib. It has an incidence of transaminitis and the problems with colitis. Of course, with all these different drugs, we worry about infectious complications. I look forward to seeing whether that gets approved soon. The other thing that might be exciting, outside the role of follicular lymphoma but by inhibiting gamma, is that perhaps we are going to extend a number of diseases that can be treated with it—perhaps into T-cell lymphomas and other malignancies.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: John mentioned the PI3-kinase inhibitors, and perhaps 1 of the appeals of this is that they have a different mechanism of action. They’re not the cytotoxic chemotherapy that we’ve been using. Matt, can you explain that a little bit?

Matthew Lunning, DO: It’s been an interesting story to watch the landscape of the PI3-kinase class take shape, starting with the delta inhibitors, and then you have the delta-gamma inhibitors, and now you have delta-alpha inhibitors. These isoforms—at least the delta-specific isoforms—were felt to be the pathway that was involved in the B-cell pathway in lymphomagenesis, regarding…the contribution that the alpha isoform brings potentially to drug resistance, but also looking at bringing in the gamma and where that may play in certain types of lymphomas. So, I think when you have now 3 agents that you’re looking at with approvals in the follicular lymphoma space and how you’re going to use them moving forward, it will be interesting to slice and dice those drugs.

Ian W. Flinn, MD, PhD: There are these 4 different isoforms. I remember originally, when we were working on idelalisib, the concern was that by using 1 isoform-specific inhibitor…you would get mechanisms of escape through some of the other isoforms. I think there are some data, at least in Mantle cell lymphoma, that that’s a real possibility. It is less clear to me in some of the others; at least it’s hard to prove one way or the other. Now there are 2 FDA-approved PI3-kinase inhibitors for follicular lymphoma, both idelalisib and copanlisib; they are different. What do you think of these? Do you think it makes a difference? One is a pure delta inhibitor; one also inhibits the alpha isoform. What are your thoughts?

Sonali M. Smith, MD: Idelalisib, as you said, is the first one that was approved and that hits delta specifically. It’s an oral agent that is approved for relapsed and refractory disease. The study that really showed its efficacy was a really strong study in terms of looking at probably the highest-risk people with follicular lymphoma; this double-refractory group of people that have refractory disease to both alkylating agents and rituximab. There you see a really nice activity and efficacy profile, but the challenge, as we’ve learned over time, is that there is also a unique toxicity profile of transaminase elevation, and some colitis that can be very severe, and pneumonitis, and there’s also infection. As an oral agent, it’s appealing, but there are these toxicities that have to be considered.

Copanlisib came along; I think there are 2 important differences from idelalisib. One is that it also targets the alpha isoforms; you get alpha and delta inhibition. The second major difference is that it’s given intravenously, and the schedule is an hour once a week for 3 weeks out of 4. So, it’s a little more of an injection burden for patients, but in terms of the CHRONOS study that you just referred to, it shows that the response rate is somewhere close to 60%. Complete response rate is low; it’s probably in the 13% to 15% rate, but it has a very different toxicity profile.

You don’t see the same transaminase elevation, but what you do see are more of the alpha effects. You see hypertension and hyperglycemia that are very transient, and I think for people who are not expecting it, it can be probably pretty shocking, because the hyperglycemia occurs very quickly after the infusion and can be quite high but then also rapidly drops. The same thing with the hypertension; you can have grade 2 or more hypertension, but again, it drops, and most people tend to be asymptomatic. Using copanlisib just needs some awareness of what toxicity to look for. All of that being said, I think the toxicity profile is favorable. These are transient effects, and I think whether or not you use one or the other probably is going to have more to do with reimbursement and patient selection, in terms of an oral versus intravenous, than anything.

Ian W. Flinn, MD, PhD: They do have very different profiles and 1 adverse event profile, so I guess 1 explanation is that it’s the different isoforms operating, right? We’re hitting delta versus delta and alpha. Other people have argued, and some of the authors on the copanlisib study had argued, that it was the schedule and not constantly hitting it. John, you’ve done a lot of work with PI3-kinase inhibitors. What’s your take on that? I’m not so sure that with any of the drugs we’re giving, we know the right dose and schedule. Maybe we should be exploring some of these other schedules with some of the drugs that we already have.

John P. Leonard, MD: Yes, I think it’s a fair point. At the end of the day, we don’t have a great sense of whether or not changing the schedule or changing the exposure to the drug will ameliorate toxicities certainly. But, from the standpoint of compromising efficacy, we don’t know. With the toxicities for both of the PI3-kinase inhibitors that are approved, the good part is that we know, and we were a little surprised with idelalisib with what occurred as far as toxicity. Now we know what can happen, and if we’re monitoring patients, the expectations are different. With copanlisib, there are some pretty well-established monitoring guidelines and some predictability as to when you have to worry about the toxicities and then when you get beyond them. In my mind, these are particularly useful drugs for older patients, and we have a lot of follicular lymphoma patients that are older. When they’ve been through a couple of different chemotherapy regimens, they’re not excited to have them; they’re not headed toward transplant. You can get good mileage, and again, with care and with monitoring, can manage the toxicities reasonably well.

Ian W. Flinn, MD, PhD: We should also talk a little bit about duvelisib. Duvelisib is a PI3-kinase, delta and gamma isoform-specific inhibitor, so it doesn’t really pick up much in the way of alpha. That’s currently in development. This is a drug that has been studied in a variety of hematological diseases, including low-grade lymphoma. In the DYNAMO study, we saw about a 50% overall response rate in that very difficult patient population that you talked about earlier, where it was the patients that were double refractory; refractory to both rituximab and to chemotherapy. I thought those were pretty exciting data. That’s before the FDA, so by October, we should know whether that one gets approved. It does have some similar toxicities that we see, perhaps with idelalisib. It has an incidence of transaminitis and the problems with colitis. Of course, with all these different drugs, we worry about infectious complications. I look forward to seeing whether that gets approved soon. The other thing that might be exciting, outside the role of follicular lymphoma but by inhibiting gamma, is that perhaps we are going to extend a number of diseases that can be treated with it—perhaps into T-cell lymphomas and other malignancies.

Transcript Edited for Clarity 
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