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Emerging BTK Inhibitors for CLL

Panelists: William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center; Steven Coutre, MD, Stanford University Medical Center; Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute; Nicole Lamanna, MD, Columbia University Medical Center; Shuo Ma, MD, PhD, Robert H. Lurie Comprehensive Cancer Center
Published: Tuesday, Jan 15, 2019



Transcript:

William G. Wierda, MD, PhD:
So ibrutinib is the big BTK [Bruton tyrosine kinase] on the block in terms of CLL treatment, BTK inhibitor. There are other BTK inhibitors, they’re in development. One is approved for mantle cell, which is acalabrutinib. We have others that are irreversible inhibitors in development, and then in earlier development there are some reversible inhibitors. So acalabrutinib probably will be the next BTK inhibitor approved for CLL. I wonder, Anthony, if you could comment on acalabrutinib and how it’s different from ibrutinib, and what are some of the studies that are ongoing that we’re expecting results from?

Anthony R. Mato, MD: Sure. So at the [American Society of Hematology Annual] Meeting [and Exposition], we saw an updated data set, presented by John Byrd, of acalabrutinib as a first therapy for patients with CLL. I think these data were particularly important as we saw earlier presentations [that] had a favorable toxicity profile, [a] very high response rate exceeding 95%, durable remissions. But it was early on, and so people argued [that] with longer follow-up, [we] would start to see a toxicity profile that looked more and more like that of ibrutinib.

Of course, it’s really difficult to perform cross-trial comparisons, particularly from the perspective of AEs [adverse effects], but the data that were presented here looked [as if] the toxicity profile remained quite favorable for acalabrutinib, and that the data in terms of progression-free survival and response also looked to be quite favorable. So [there are] very interesting data.

In terms of trials that are in development for acalabrutinib, there [are 2] that come to mind. There’s a frontline trial, [with] essentially the exact same comparison that we saw with iLLUMINATE. So that’ll be interesting from when those data become available in terms of helping us to decide what [acalabrutinib] looks like with the CD20 in the frontline setting and what that AE profile looks like relative to what we saw with ibrutinib.

I think the more interesting trial is in the relapsed [or] refractory setting, where there’s a head-to-head comparison. In high-risk patients with relapsed [or] refractory disease, I believe they had to have del 17p or del 11q, 1-to-1 comparison against ibrutinib. And there, we’ll really get a window I think into what the AE profile looks like for 1 versus another.
You know, I think 1 of the lessons learned from the ibrutinib trial is that the toxicity was, specific to ibrutinib, not really as evident until we had randomized comparisons. And so obviously not against another BTK inhibitor. So I think looking at rates of hypertension, [AF; atrial fibrillation], bleeding, arthralgia for example, in that patient population will really shed light on to how we should be thinking about sequencing or selecting 1 drug versus another. I think those are the 2 standout trials, unless anyone has another that comes to mind for [acalabrutinib], but I agree, very interesting data with that compound.

Alexey V. Danilov, MD, PhD: So in this study there was 6% atrial fibrillation incidence and 17% hypertension. With ibrutinib, now we know that atrial fibrillation rates are up to 12%, 16%. So do you think this is different? What is your sense of this, or do we just not know?

Anthony R. Mato, MD: So I can speak to it from my own experience, which has been, I haven’t seen those toxicities per se in small numbers of patients, which makes it [even] less relevant. And then from the clinical trial experience, I hate to speculate because of the fact that follow-up is different [and] patients are different, especially given [that] within a year we’ll probably have randomized data that will help people really make conclusions. So I think at this point it’s speculative. I think the data presented stand-alone were encouraging, but I sort of refused to say 1 drug is better tolerated than the other because I don’t think it’s appropriate.

Susan M. O’Brien, MD: And the thing about [AF] is that, well 2 things, and you’d really have to look at the cases to know this, but 1 is that in these older patients, probably if you have enough patients on the trial, somebody is going to develop [AF] no matter what the drug is.

Anthony R. Mato, MD: Guaranteed.

Susan M. O’Brien, MD: But 6% is probably a bit higher, maybe, than might be expected. The other point is, and I remember this because in the earlier days of acalabrutinib, the first patient I’m aware of [who] developed [AF] was septic in the ICU [intensive care unit]. So we all know that [AF] is a complication of people [who] are quite sick or have pneumonia, and it may be more related to that than the actual drug in that setting. So again, I agree with Anthony. This is where the randomized head-to-head will be important, particularly because even if the incidence of [AF] with ibrutinib is 10% or 12%, that’s still low considering that means the flip side of that is 88%, 90% don’t get [AF]. So whenever you’re dealing with these low-frequency toxicities, you really need a lot of patients to make your confidence intervals narrow around what you really think it is.
So I did think 6% in this trial might be a bit higher than I would expect for somebody not on a BTK inhibitor. Is 6% different [from] 10%? Hopefully that’s the kind of data that we would get from the randomized trial.

Anthony R. Mato, MD: Of course, the other message from all of us is that I think most of us believe that many of these toxicities are quite manageable. So just because [AF] happens in 6% versus 8%, I don’t know [if] that would for sure define which drug I would use for a patient. There’s a lot more that would go into the decision making.

Alexey V. Danilov, MD, PhD: I think some of those toxicities and comparisons will be difficult to tease out, even in a setting of a randomized study as we group together grade 1 [and] 2 toxicities and grade 3 [and] 4 toxicities. And if we are looking for [a] fine distinction there, I think even in a randomized study it may be difficult to get a clear impression of what it looks like.

Matthew S. Davids, MD, MMSc: Which in and of itself would be telling. If it’s so hard to discern a difference, then maybe it’s not a big difference. [That] is clinically meaningful.

Transcript Edited for Clarity.

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Transcript:

William G. Wierda, MD, PhD:
So ibrutinib is the big BTK [Bruton tyrosine kinase] on the block in terms of CLL treatment, BTK inhibitor. There are other BTK inhibitors, they’re in development. One is approved for mantle cell, which is acalabrutinib. We have others that are irreversible inhibitors in development, and then in earlier development there are some reversible inhibitors. So acalabrutinib probably will be the next BTK inhibitor approved for CLL. I wonder, Anthony, if you could comment on acalabrutinib and how it’s different from ibrutinib, and what are some of the studies that are ongoing that we’re expecting results from?

Anthony R. Mato, MD: Sure. So at the [American Society of Hematology Annual] Meeting [and Exposition], we saw an updated data set, presented by John Byrd, of acalabrutinib as a first therapy for patients with CLL. I think these data were particularly important as we saw earlier presentations [that] had a favorable toxicity profile, [a] very high response rate exceeding 95%, durable remissions. But it was early on, and so people argued [that] with longer follow-up, [we] would start to see a toxicity profile that looked more and more like that of ibrutinib.

Of course, it’s really difficult to perform cross-trial comparisons, particularly from the perspective of AEs [adverse effects], but the data that were presented here looked [as if] the toxicity profile remained quite favorable for acalabrutinib, and that the data in terms of progression-free survival and response also looked to be quite favorable. So [there are] very interesting data.

In terms of trials that are in development for acalabrutinib, there [are 2] that come to mind. There’s a frontline trial, [with] essentially the exact same comparison that we saw with iLLUMINATE. So that’ll be interesting from when those data become available in terms of helping us to decide what [acalabrutinib] looks like with the CD20 in the frontline setting and what that AE profile looks like relative to what we saw with ibrutinib.

I think the more interesting trial is in the relapsed [or] refractory setting, where there’s a head-to-head comparison. In high-risk patients with relapsed [or] refractory disease, I believe they had to have del 17p or del 11q, 1-to-1 comparison against ibrutinib. And there, we’ll really get a window I think into what the AE profile looks like for 1 versus another.
You know, I think 1 of the lessons learned from the ibrutinib trial is that the toxicity was, specific to ibrutinib, not really as evident until we had randomized comparisons. And so obviously not against another BTK inhibitor. So I think looking at rates of hypertension, [AF; atrial fibrillation], bleeding, arthralgia for example, in that patient population will really shed light on to how we should be thinking about sequencing or selecting 1 drug versus another. I think those are the 2 standout trials, unless anyone has another that comes to mind for [acalabrutinib], but I agree, very interesting data with that compound.

Alexey V. Danilov, MD, PhD: So in this study there was 6% atrial fibrillation incidence and 17% hypertension. With ibrutinib, now we know that atrial fibrillation rates are up to 12%, 16%. So do you think this is different? What is your sense of this, or do we just not know?

Anthony R. Mato, MD: So I can speak to it from my own experience, which has been, I haven’t seen those toxicities per se in small numbers of patients, which makes it [even] less relevant. And then from the clinical trial experience, I hate to speculate because of the fact that follow-up is different [and] patients are different, especially given [that] within a year we’ll probably have randomized data that will help people really make conclusions. So I think at this point it’s speculative. I think the data presented stand-alone were encouraging, but I sort of refused to say 1 drug is better tolerated than the other because I don’t think it’s appropriate.

Susan M. O’Brien, MD: And the thing about [AF] is that, well 2 things, and you’d really have to look at the cases to know this, but 1 is that in these older patients, probably if you have enough patients on the trial, somebody is going to develop [AF] no matter what the drug is.

Anthony R. Mato, MD: Guaranteed.

Susan M. O’Brien, MD: But 6% is probably a bit higher, maybe, than might be expected. The other point is, and I remember this because in the earlier days of acalabrutinib, the first patient I’m aware of [who] developed [AF] was septic in the ICU [intensive care unit]. So we all know that [AF] is a complication of people [who] are quite sick or have pneumonia, and it may be more related to that than the actual drug in that setting. So again, I agree with Anthony. This is where the randomized head-to-head will be important, particularly because even if the incidence of [AF] with ibrutinib is 10% or 12%, that’s still low considering that means the flip side of that is 88%, 90% don’t get [AF]. So whenever you’re dealing with these low-frequency toxicities, you really need a lot of patients to make your confidence intervals narrow around what you really think it is.
So I did think 6% in this trial might be a bit higher than I would expect for somebody not on a BTK inhibitor. Is 6% different [from] 10%? Hopefully that’s the kind of data that we would get from the randomized trial.

Anthony R. Mato, MD: Of course, the other message from all of us is that I think most of us believe that many of these toxicities are quite manageable. So just because [AF] happens in 6% versus 8%, I don’t know [if] that would for sure define which drug I would use for a patient. There’s a lot more that would go into the decision making.

Alexey V. Danilov, MD, PhD: I think some of those toxicities and comparisons will be difficult to tease out, even in a setting of a randomized study as we group together grade 1 [and] 2 toxicities and grade 3 [and] 4 toxicities. And if we are looking for [a] fine distinction there, I think even in a randomized study it may be difficult to get a clear impression of what it looks like.

Matthew S. Davids, MD, MMSc: Which in and of itself would be telling. If it’s so hard to discern a difference, then maybe it’s not a big difference. [That] is clinically meaningful.

Transcript Edited for Clarity.
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