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BTK Inhibitors in R/R CLL

Panelists: Nicole Lamanna, MD, Herbert Irving Comprehensive Cancer Center at Columbia University; Farrukh Awan, MD, University of Texas Southwestern Medical Center; Jan Burger, MD, PhD, The University of Texas MD Anderson Cancer Center; Richard R. Furman, MD, NewYork-Presbyterian Medical Center; Javier A. Pinilla-Ibarz, MD, PhD, H. Lee Moffitt Cancer Center
Published: Thursday, Feb 27, 2020



Transcript: 

Nicole Lamanna, MD: Anybody want to comment about the ASCEND trial or acalabrutinib in this setting?

Richard R. Furman, MD: I guess we could say the ASCEND trial is a trial that was really done for no good science. It really was just done to get approval for acalabrutinib in the relapsed. In my opinion, acalabrutinib has already established itself. One of the questions is now that we have HELIOS data or now that we have the Alliance study and ECOG study, do we really need to do that with each novel agent? It would be unfortunate if we really had to make every novel agent go through exactly the same hoops each time.

Farrukh Awan, MD: One advantage I felt that this provided us were the idelalisib data. I think most of the patients who were in the control group were treated with idelalisib, rituximab. A lot of times that question gets asked, “Hey, what’s the right next treatment, second-line treatment, is it ibrutinib, or BTK [Bruton tyrosine kinase] inhibitor, or acalabrutinib, or is it a PI3 kinase inhibitor pathway?” Even though the study wasn’t designed to address that specific question, again we have some information that it appeared to be better than a PI3 kinase-containing regimen, for what it’s worth. I think that was probably a useful piece of information. I think nobody was denying the efficacy of acalabrutinib, and we expected it to be better than the competition.

Nicole Lamanna, MD: For patients who had chemoimmunotherapy frontline and then relapse, still a BTKi [BTK inhibitor] over a PI3?

Farrukh Awan, MD: That would be my approach.

Richard R. Furman, MD: The thing to remember though, as I stated earlier, BTK inhibitor therapy is my first choice therapy for upfront patients. If I have a relapsed patient who hasn’t yet seen a BTK inhibitor therapy….

Nicole Lamanna, MD: Then you’re going to give them a BTK, yes.

Richard R. Furman, MD: Absolutely. While this study is perhaps one of the few studies that compared BTK inhibitor therapy to PI3 kinase inhibitor therapy, the drugs have very different long-term outcomes. The follow-up for BTK inhibitor therapy is far superior than it is for all the PI3 kinase inhibitors. At this point, we really have no reason to feel the need to compare the 2 of them.

Javier A. Pinilla-Ibarz, MD, PhD: Unfortunately, I think these trials corroborate what we have seen in the previous trials that you have done with idelalisib, that the reason that people discontinue is toxicity. It’s always the argument what’s happened with a PI3K that can be tolerated over time in terms of how similar they may be in the future. We always discuss different pathways, but at the same time, I think what we encounter with the available PI3K delta-gamma-delta is the tolerability, which really somewhat limits the durability of these response. This is another test or another trial to really address that.

Nicole Lamanna, MD: Intolerance to a BTKi. Now, we talked about how you can go from, with some of the acalabrutinib data, you can go from possibly ibrutinib to acalabrutinib with intolerance. What about a BTKi for intolerance to a PI3 kinase inhibitor?

Javier A. Pinilla-Ibarz, MD, PhD: Well, I think it’s been shown, at least in the retrospective data, and…the data look very good because again, it’s one of the main reasons. However, we don’t have this PI3K mostly used in the frontline. We are talking a different kind of patients, patients who maybe already have chemotherapy, maybe already getting a PI3K. Maybe we know that the delay of the BTK therapy through the lines of therapies in the really long-term data, also is somewhat detrimental for the effect, maybe not much in the intolerance but definitely in the resistance.

Richard R. Furman, MD: One of the things to also keep in mind with all that is certainly we do have idelalisib upfront data.

Nicole Lamanna, MD: We do.

Richard R. Furman, MD: What I think is going to be interesting…PI3 kinase inhibitors are likely easier to combine with BCL2 [B-cell lymphoma 2 protein] inhibitor therapy, and if we’re just asking the BTK inhibitor or the PI3 kinase inhibitor to make the BCL2 inhibitor more efficacious, those are combinations that really might be very effective. We have duvelisib, acalabrutinib studies ongoing. We have ibrutinib and duvelisib studies going on, and we have an umbralisib, venetoclax study ongoing as well. Even because our PFS [progression-free survival] might be shorter, it doesn’t necessarily mean that the drug itself is not going to be excellent to combine with another agent.

Nicole Lamanna, MD: There’s still a potential role for PI3 kinase inhibitors, and hopefully some of these future studies will evaluate those combinations.

Richard R. Furman, MD: Especially in these people who have cardiac issues and bleeding issues, we might need to look for another therapy beyond the BTK inhibitors.

Transcript Edited for Clarity

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Transcript: 

Nicole Lamanna, MD: Anybody want to comment about the ASCEND trial or acalabrutinib in this setting?

Richard R. Furman, MD: I guess we could say the ASCEND trial is a trial that was really done for no good science. It really was just done to get approval for acalabrutinib in the relapsed. In my opinion, acalabrutinib has already established itself. One of the questions is now that we have HELIOS data or now that we have the Alliance study and ECOG study, do we really need to do that with each novel agent? It would be unfortunate if we really had to make every novel agent go through exactly the same hoops each time.

Farrukh Awan, MD: One advantage I felt that this provided us were the idelalisib data. I think most of the patients who were in the control group were treated with idelalisib, rituximab. A lot of times that question gets asked, “Hey, what’s the right next treatment, second-line treatment, is it ibrutinib, or BTK [Bruton tyrosine kinase] inhibitor, or acalabrutinib, or is it a PI3 kinase inhibitor pathway?” Even though the study wasn’t designed to address that specific question, again we have some information that it appeared to be better than a PI3 kinase-containing regimen, for what it’s worth. I think that was probably a useful piece of information. I think nobody was denying the efficacy of acalabrutinib, and we expected it to be better than the competition.

Nicole Lamanna, MD: For patients who had chemoimmunotherapy frontline and then relapse, still a BTKi [BTK inhibitor] over a PI3?

Farrukh Awan, MD: That would be my approach.

Richard R. Furman, MD: The thing to remember though, as I stated earlier, BTK inhibitor therapy is my first choice therapy for upfront patients. If I have a relapsed patient who hasn’t yet seen a BTK inhibitor therapy….

Nicole Lamanna, MD: Then you’re going to give them a BTK, yes.

Richard R. Furman, MD: Absolutely. While this study is perhaps one of the few studies that compared BTK inhibitor therapy to PI3 kinase inhibitor therapy, the drugs have very different long-term outcomes. The follow-up for BTK inhibitor therapy is far superior than it is for all the PI3 kinase inhibitors. At this point, we really have no reason to feel the need to compare the 2 of them.

Javier A. Pinilla-Ibarz, MD, PhD: Unfortunately, I think these trials corroborate what we have seen in the previous trials that you have done with idelalisib, that the reason that people discontinue is toxicity. It’s always the argument what’s happened with a PI3K that can be tolerated over time in terms of how similar they may be in the future. We always discuss different pathways, but at the same time, I think what we encounter with the available PI3K delta-gamma-delta is the tolerability, which really somewhat limits the durability of these response. This is another test or another trial to really address that.

Nicole Lamanna, MD: Intolerance to a BTKi. Now, we talked about how you can go from, with some of the acalabrutinib data, you can go from possibly ibrutinib to acalabrutinib with intolerance. What about a BTKi for intolerance to a PI3 kinase inhibitor?

Javier A. Pinilla-Ibarz, MD, PhD: Well, I think it’s been shown, at least in the retrospective data, and…the data look very good because again, it’s one of the main reasons. However, we don’t have this PI3K mostly used in the frontline. We are talking a different kind of patients, patients who maybe already have chemotherapy, maybe already getting a PI3K. Maybe we know that the delay of the BTK therapy through the lines of therapies in the really long-term data, also is somewhat detrimental for the effect, maybe not much in the intolerance but definitely in the resistance.

Richard R. Furman, MD: One of the things to also keep in mind with all that is certainly we do have idelalisib upfront data.

Nicole Lamanna, MD: We do.

Richard R. Furman, MD: What I think is going to be interesting…PI3 kinase inhibitors are likely easier to combine with BCL2 [B-cell lymphoma 2 protein] inhibitor therapy, and if we’re just asking the BTK inhibitor or the PI3 kinase inhibitor to make the BCL2 inhibitor more efficacious, those are combinations that really might be very effective. We have duvelisib, acalabrutinib studies ongoing. We have ibrutinib and duvelisib studies going on, and we have an umbralisib, venetoclax study ongoing as well. Even because our PFS [progression-free survival] might be shorter, it doesn’t necessarily mean that the drug itself is not going to be excellent to combine with another agent.

Nicole Lamanna, MD: There’s still a potential role for PI3 kinase inhibitors, and hopefully some of these future studies will evaluate those combinations.

Richard R. Furman, MD: Especially in these people who have cardiac issues and bleeding issues, we might need to look for another therapy beyond the BTK inhibitors.

Transcript Edited for Clarity
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