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PI3K 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: Now, for BTK [Bruton tyrosine kinase], not intolerant patients, but progressive patients, would you recommend a PI3 kinase inhibitor in that circumstance?

Jan Burger, MD, PhD: No, I think what’s established, the BCL2 [B-cell lymphoma 2 protein], venetoclax, that’s established to work and has I think acceptable durability of response. Those patients respond, I think about maybe 70%, 80% of patients, but there’s a drop-off over time, so those patients probably also need to be worked up for cell therapy if they come into that situation. To your question, is there an alternative to the BCL2 antagonists, I think there are no larger datasets; there are some real-world data that Anthony Mato, MD, MSCE, was presenting where I think there can be some responses. My reading of the data, they are short-lived. It’s not very effective to use a PI3 kinase inhibitor in a patient who is starting to fail on a BTK inhibitor, so the established way would be to go with venetoclax.

Nicole Lamanna, MD: So for intolerance, there are multiple options for therapy, whether it be perhaps a second-generation BTK inhibitor [BTKi], PI3 kinase inhibitor, or other. For progressive disease to a BTK inhibitor, probably not a good switch to a PI3, unless it’s maybe with a combination.

But as a monotherapy probably not because the response duration from the data that we have is pretty short if you failed a BTKi to go just to a PI3 kinase inhibitor as monotherapy.

Richard R. Furman, MD: But remember in combination with a BCL2 inhibitor.

Nicole Lamanna, MD: That may be a different issue.

Richard R. Furman, MD: I’m not so sure the anti-CD20 combinations add much.

Nicole Lamanna, MD: Fair enough.

Richard R. Furman, MD: It’s important to emphasize that.

Nicole Lamanna, MD: Fair enough. Are folks using duvelisib as monotherapy in your relapsed patients since that’s approved?

Farrukh Awan, MD: I’ll also add to the discussion we just had. I feel that PI3 kinase inhibitors are very active compounds. I think they were our first foray into this whole arena, and unfortunately, there were toxicity issues. I think we’ve all seen the data where when you dose interrupt or you dose decrease, you don’t necessarily have an inferior outcome. There could be some argument that we might have had the dose wrong all along, that we might have gone off with maybe a drug holiday or a lower dose in both of those drugs, that their selecting the DLT [dose-limiting toxicity] model of trials was probably not the right thing to do in this class of drugs because of the toxicity and the mechanisms of toxicity. I haven’t given up on PI3 kinase inhibitors.

Nicole Lamanna, MD: Many of us have been involved in that.

Farrukh Awan, MD: Yes, and we’ve all seen the toxicity. I think there are 2 issues here, first is it’s a great drug. We need to figure out exactly how to dose it properly. Secondly, we also need to know how to manage the toxicities aggressively and before they get into the grade 3 and 4 toxicity that end with the patient being admitted to the hospital with really bad diarrhea. I think we have to realize both of those. Unfortunately, the way it stands is that the PI3 kinase inhibitors, both idelalisib or duvelisib, they have fairly similar efficacy and fairly similar toxicity profiles. They have a small role in the management of our relapsed/refractory patients.

I still feel that they are fairly reasonable choices in somebody who may not be a candidate for venetoclax or PI3 kinase inhibitors. Yes, we do know that young patients with untreated disease should not get these agents in the first-line setting. There are data for the older patient untreated setting that seem to suggest that they might be OK tolerated. I shouldn’t say well tolerated, but their adverse
effects may not be as bad as you see in younger patients.

I think there are a lot of things that we don’t quite understand with PI3 kinase inhibitors. I still feel that that’s a perfectly reasonable choice for a lot of our patients, because here’s the issue, if you have a person failing BTK inhibitors and possibly venetoclax, what do you do?

Nicole Lamanna, MD: That’s a good segue to the next topic.

Farrukh Awan, MD: If you don’t have access to CAR [chimeric antigen receptor] T-cell therapy or they’re not candidates, which a lot of our patients are not candidates for allogeneic transplant, what do you do for those patients? Do you go back to chemotherapy? I don’t know if that’s the right answer.

Transcript Edited for Clarity

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Transcript: 

Nicole Lamanna, MD: Now, for BTK [Bruton tyrosine kinase], not intolerant patients, but progressive patients, would you recommend a PI3 kinase inhibitor in that circumstance?

Jan Burger, MD, PhD: No, I think what’s established, the BCL2 [B-cell lymphoma 2 protein], venetoclax, that’s established to work and has I think acceptable durability of response. Those patients respond, I think about maybe 70%, 80% of patients, but there’s a drop-off over time, so those patients probably also need to be worked up for cell therapy if they come into that situation. To your question, is there an alternative to the BCL2 antagonists, I think there are no larger datasets; there are some real-world data that Anthony Mato, MD, MSCE, was presenting where I think there can be some responses. My reading of the data, they are short-lived. It’s not very effective to use a PI3 kinase inhibitor in a patient who is starting to fail on a BTK inhibitor, so the established way would be to go with venetoclax.

Nicole Lamanna, MD: So for intolerance, there are multiple options for therapy, whether it be perhaps a second-generation BTK inhibitor [BTKi], PI3 kinase inhibitor, or other. For progressive disease to a BTK inhibitor, probably not a good switch to a PI3, unless it’s maybe with a combination.

But as a monotherapy probably not because the response duration from the data that we have is pretty short if you failed a BTKi to go just to a PI3 kinase inhibitor as monotherapy.

Richard R. Furman, MD: But remember in combination with a BCL2 inhibitor.

Nicole Lamanna, MD: That may be a different issue.

Richard R. Furman, MD: I’m not so sure the anti-CD20 combinations add much.

Nicole Lamanna, MD: Fair enough.

Richard R. Furman, MD: It’s important to emphasize that.

Nicole Lamanna, MD: Fair enough. Are folks using duvelisib as monotherapy in your relapsed patients since that’s approved?

Farrukh Awan, MD: I’ll also add to the discussion we just had. I feel that PI3 kinase inhibitors are very active compounds. I think they were our first foray into this whole arena, and unfortunately, there were toxicity issues. I think we’ve all seen the data where when you dose interrupt or you dose decrease, you don’t necessarily have an inferior outcome. There could be some argument that we might have had the dose wrong all along, that we might have gone off with maybe a drug holiday or a lower dose in both of those drugs, that their selecting the DLT [dose-limiting toxicity] model of trials was probably not the right thing to do in this class of drugs because of the toxicity and the mechanisms of toxicity. I haven’t given up on PI3 kinase inhibitors.

Nicole Lamanna, MD: Many of us have been involved in that.

Farrukh Awan, MD: Yes, and we’ve all seen the toxicity. I think there are 2 issues here, first is it’s a great drug. We need to figure out exactly how to dose it properly. Secondly, we also need to know how to manage the toxicities aggressively and before they get into the grade 3 and 4 toxicity that end with the patient being admitted to the hospital with really bad diarrhea. I think we have to realize both of those. Unfortunately, the way it stands is that the PI3 kinase inhibitors, both idelalisib or duvelisib, they have fairly similar efficacy and fairly similar toxicity profiles. They have a small role in the management of our relapsed/refractory patients.

I still feel that they are fairly reasonable choices in somebody who may not be a candidate for venetoclax or PI3 kinase inhibitors. Yes, we do know that young patients with untreated disease should not get these agents in the first-line setting. There are data for the older patient untreated setting that seem to suggest that they might be OK tolerated. I shouldn’t say well tolerated, but their adverse
effects may not be as bad as you see in younger patients.

I think there are a lot of things that we don’t quite understand with PI3 kinase inhibitors. I still feel that that’s a perfectly reasonable choice for a lot of our patients, because here’s the issue, if you have a person failing BTK inhibitors and possibly venetoclax, what do you do?

Nicole Lamanna, MD: That’s a good segue to the next topic.

Farrukh Awan, MD: If you don’t have access to CAR [chimeric antigen receptor] T-cell therapy or they’re not candidates, which a lot of our patients are not candidates for allogeneic transplant, what do you do for those patients? Do you go back to chemotherapy? I don’t know if that’s the right answer.

Transcript Edited for Clarity
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