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Ibrutinib + Venetoclax for Frontline 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 13, 2020



Transcript: 

Nicole Lamanna, MD: Before we hit relapsed, let’s briefly discuss doublets or triplets in frontline setting. Let’s talk a little about the CAPTIVATE study, the combination of ibrutinib and venetoclax, and the high responses that we saw. What do you think about that? Folks are very interested in obviously taking away all intravenous IV therapy and doing 2 orals, 2 novel targeted agents together, limited duration of therapy. Is that ready for prime time?

Jan Burger, MD, PhD: I don’t think it’s ready for prime time. There are exciting data because we get patients into deeper remissions with a nonchemotherapy regimen. Most patients, at least in the frontline setting, become MRD negative in blood and in bone marrow. That’s a gateway to limited-duration treatment. The problem there could be, first it is more toxic. The toxicities add up. Then we don’t have any long-term follow-up data, and we know single-agent treated patients with ibrutinib in particular or with BTK inhibitors have very good outcome with a single-agent therapy. We just don’t know if the outcome is going to be definitely better. Is there maybe a cure fraction? I guess that’s what the hope is. But unless we have longer-term follow-up, I would not recommend that.

Javier A. Pinilla-Ibarz, MD, PhD: I really concur.

Nicole Lamanna, MD: I do want to hear this one.

Javier A. Pinilla-Ibarz, MD, PhD: Sure.

Nicole Lamanna, MD: There are very nice data out of The University of Texas MD Anderson Cancer Center and from the CAPTIVATE trial.

Richard R. Furman, MD: Absolutely. The combination of ibrutinib and venetoclax is extraordinarily powerful. Tolerability does become an issue, and that certainly is something results from not just drug-drug interactions but overlapping toxicities. One of the important questions I liked is whether we can find a better combination. Acalabrutinib-venetoclax, umbralisib-venetoclax, duvelisib-venetoclax: these are different combinations that may yield very excellent results with far better tolerability. I very much enjoy not having to put IVs into my patients, so I think the total lack of intravenous component is an important part of that therapy.

I just want to highlight the data from Jennifer Woyach, of The Ohio State University Comprehensive Cancer Center, looking at reasons for treatment discontinuation for patients on ibrutinib. Their estimate was that if you were not 17p deleted, did not have a complex karyotype and were over age 65, you had a 98.2% chance of being free from progression on single-agent ibrutinib. For those people, we really could never do better. A lot of what we’re talking about are for the other patients, the patients who mainly represent about 20% of CLL [chronic lymphocytic leukemia] overall. When we do start looking at these data, it’s going to be important to identify that the whole population of CLL patients might not yield the data, because they’re not going to be enriched for the ones who may actually benefit. I can see 1 day us being able to say, “Well, you only need single-agent ibrutinib but you need ibrutinib-venetoclax or some BCR/BCL2 combination.”

Nicole Lamanna, MD: That raises the question, obviously in frontline setting, given that we need much more mature data, does everybody with CLL need a doublet or a triplet? Farrukh?

Farrukh Awan, MD: Ultimately there might be a combination strategy that we’ll all use, but at this point I still don’t feel that it adds substantially to all the other drugs we have. We just need to give it more time. Then the other argument that happens is if I use all 3 of my most active agents up front, how do I salvage those patients upon relapse. Can I re-treat them? Can I switch agents? I think those are again questions that still need to be addressed. We have preliminary data on those, but we don’t have systematic trials addressing this question. Time-limited therapy with 3 drugs, stop, and then re-treat upon relapse, and what’s a long-term outcome? I think all those are interesting questions. Does that change my practice right now outside of a clinical trial? The answer is no.

Javier A. Pinilla-Ibarz, MD, PhD: The thing I want to add is that for sure, the data and the long-term data with ibrutinib are very strong. We have many patients doing very well. We need to go back to the timing with the therapy versus long-term therapy. I think something of the widely interesting in our patients. I was also caught by the attention of 1 of the abstracts presented on the addition of venetoclax with a goal to discontinue ibrutinib. It’s something that in the future obviously is a research question, but I think we’re going to see it more and more. Also, really going back to the fact that the mechanism of action of BTK inhibitors and BCL2 inhibitors, is quite complementary and, in my opinion, also really addresses 2 different compartments.

At some point, and we’re going to see these kinds of trials more and more, adding a second agent mainly for a certain period of time, so patients can really ultimately discontinue therapy. Once again, classically we always really try to. It is true that there’s always concern when you really put everything in the beginning. At the end of the day, historically in medicine, we try to incorporate the best therapies alone or in combination sooner, and we have better and better data. It’s true that it’s hard to really beat this 98%, but we are going to the fact that, well, our chronic toxicities may impact the quality of life in our patients, so we need to really start to be thinking about these trials in the future.

Nicole Lamanna, MD: There might be some subgroups that might benefit from a doublet or a triplet up front.
Javier A. Pinilla-Ibarz, MD, PhD: Absolutely.

Nicole Lamanna, MD: But the data are still immature.
Javier A. Pinilla-Ibarz, MD, PhD: Absolutely. Again, I think we need timing of therapy. And even financing and toxicities are some things that are going to really pan out in the future, in my opinion.

Transcript Edited for Clarity

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Transcript: 

Nicole Lamanna, MD: Before we hit relapsed, let’s briefly discuss doublets or triplets in frontline setting. Let’s talk a little about the CAPTIVATE study, the combination of ibrutinib and venetoclax, and the high responses that we saw. What do you think about that? Folks are very interested in obviously taking away all intravenous IV therapy and doing 2 orals, 2 novel targeted agents together, limited duration of therapy. Is that ready for prime time?

Jan Burger, MD, PhD: I don’t think it’s ready for prime time. There are exciting data because we get patients into deeper remissions with a nonchemotherapy regimen. Most patients, at least in the frontline setting, become MRD negative in blood and in bone marrow. That’s a gateway to limited-duration treatment. The problem there could be, first it is more toxic. The toxicities add up. Then we don’t have any long-term follow-up data, and we know single-agent treated patients with ibrutinib in particular or with BTK inhibitors have very good outcome with a single-agent therapy. We just don’t know if the outcome is going to be definitely better. Is there maybe a cure fraction? I guess that’s what the hope is. But unless we have longer-term follow-up, I would not recommend that.

Javier A. Pinilla-Ibarz, MD, PhD: I really concur.

Nicole Lamanna, MD: I do want to hear this one.

Javier A. Pinilla-Ibarz, MD, PhD: Sure.

Nicole Lamanna, MD: There are very nice data out of The University of Texas MD Anderson Cancer Center and from the CAPTIVATE trial.

Richard R. Furman, MD: Absolutely. The combination of ibrutinib and venetoclax is extraordinarily powerful. Tolerability does become an issue, and that certainly is something results from not just drug-drug interactions but overlapping toxicities. One of the important questions I liked is whether we can find a better combination. Acalabrutinib-venetoclax, umbralisib-venetoclax, duvelisib-venetoclax: these are different combinations that may yield very excellent results with far better tolerability. I very much enjoy not having to put IVs into my patients, so I think the total lack of intravenous component is an important part of that therapy.

I just want to highlight the data from Jennifer Woyach, of The Ohio State University Comprehensive Cancer Center, looking at reasons for treatment discontinuation for patients on ibrutinib. Their estimate was that if you were not 17p deleted, did not have a complex karyotype and were over age 65, you had a 98.2% chance of being free from progression on single-agent ibrutinib. For those people, we really could never do better. A lot of what we’re talking about are for the other patients, the patients who mainly represent about 20% of CLL [chronic lymphocytic leukemia] overall. When we do start looking at these data, it’s going to be important to identify that the whole population of CLL patients might not yield the data, because they’re not going to be enriched for the ones who may actually benefit. I can see 1 day us being able to say, “Well, you only need single-agent ibrutinib but you need ibrutinib-venetoclax or some BCR/BCL2 combination.”

Nicole Lamanna, MD: That raises the question, obviously in frontline setting, given that we need much more mature data, does everybody with CLL need a doublet or a triplet? Farrukh?

Farrukh Awan, MD: Ultimately there might be a combination strategy that we’ll all use, but at this point I still don’t feel that it adds substantially to all the other drugs we have. We just need to give it more time. Then the other argument that happens is if I use all 3 of my most active agents up front, how do I salvage those patients upon relapse. Can I re-treat them? Can I switch agents? I think those are again questions that still need to be addressed. We have preliminary data on those, but we don’t have systematic trials addressing this question. Time-limited therapy with 3 drugs, stop, and then re-treat upon relapse, and what’s a long-term outcome? I think all those are interesting questions. Does that change my practice right now outside of a clinical trial? The answer is no.

Javier A. Pinilla-Ibarz, MD, PhD: The thing I want to add is that for sure, the data and the long-term data with ibrutinib are very strong. We have many patients doing very well. We need to go back to the timing with the therapy versus long-term therapy. I think something of the widely interesting in our patients. I was also caught by the attention of 1 of the abstracts presented on the addition of venetoclax with a goal to discontinue ibrutinib. It’s something that in the future obviously is a research question, but I think we’re going to see it more and more. Also, really going back to the fact that the mechanism of action of BTK inhibitors and BCL2 inhibitors, is quite complementary and, in my opinion, also really addresses 2 different compartments.

At some point, and we’re going to see these kinds of trials more and more, adding a second agent mainly for a certain period of time, so patients can really ultimately discontinue therapy. Once again, classically we always really try to. It is true that there’s always concern when you really put everything in the beginning. At the end of the day, historically in medicine, we try to incorporate the best therapies alone or in combination sooner, and we have better and better data. It’s true that it’s hard to really beat this 98%, but we are going to the fact that, well, our chronic toxicities may impact the quality of life in our patients, so we need to really start to be thinking about these trials in the future.

Nicole Lamanna, MD: There might be some subgroups that might benefit from a doublet or a triplet up front.
Javier A. Pinilla-Ibarz, MD, PhD: Absolutely.

Nicole Lamanna, MD: But the data are still immature.
Javier A. Pinilla-Ibarz, MD, PhD: Absolutely. Again, I think we need timing of therapy. And even financing and toxicities are some things that are going to really pan out in the future, in my opinion.

Transcript Edited for Clarity
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