ONCAlert | Upfront Therapy for mRCC

Other BTK Inhibitors in Chronic Lymphocytic Leukemia

Targeted Oncology
Published Online:12:31 PM, Wed July 3, 2019

Harry P. Erba, MD, PhD: It is a little bit more complicated. There are other differences between chemotherapy and the BTK [Bruton tyrosine kinase] inhibitors. Let’s come back to that question when we get to toxicity profiles and comparing toxicities, like in the ECOG and the Alliance trials. Let’s move on to talking about the second approved BTK inhibitor, and that’s acalabrutinib.

Anthony R. Mato, MD, MSCE: Acalabrutinib is approved only for mantle cell lymphoma in the relapsed/refractory setting. It is not yet approved for CLL [chronic lymphocytic leukemia]. There have been registrational trials, which I hear are completed and may soon be reported on, but there is no indication for CLL just yet. It probably is used in a small proportion of patients off-label, maybe in ibrutinib-intolerant patients, specifically. But at this time, we don’t have any head-to-head data or any real-world data on acalabrutinib use in CLL.

Harry P. Erba, MD, PhD: What’s your experience been like in those ibrutinib-intolerant patients?

Anthony R. Mato, MD, MSCE: I’ve only used it a few times. I was part of the head-to-head trial versus ibrutinib, which has not yet reported. But I use it occasionally in some intolerant patients. For some patients, it’s a good answer. I think it may depend on the toxicity, but it’s limited in use so far.

Harry P. Erba, MD, PhD: Do you think there’s any reason to expect, or have you seen activity of acalabrutinib in patients who have been refractory or resistant to ibrutinib?

Anthony R. Mato, MD, MSCE: Probably not high expectations. You know, the resistance mechanisms to ibrutinib are still being worked out. There are C481S mutations in BTK, which if they’re affecting ibrutinib’s binding, should probably equally affect acalabrutinib’s binding. There are downstream mutations in PLC-gamma-2, which is downstream of BTK in the signaling pathway, which should be independent of both drugs. I think it’s still a bit of a black box. Although people originally thought that these 2 types of mutations represented all progressions, outside of transformation, it’s probably not the case.

Probably half of the progressions that we see do not have either mutation present. So it’s hard to know whether 1 drug would overcome it universally. But I think biologically there’s a low expectation for somebody who truly has ibrutinib resistance, that another covalently binding BTK inhibitor, either acalabrutinib or zanubrutinib, would overcome that.

Harry P. Erba, MD, PhD: OK. Do you think there’s a role for doing BTK mutational analysis? Do you do it?

Anthony R. Mato, MD, MSCE: I do think there is a role for it. I think it’s emerging. There are some centers where they check patients every 3 months. The problem is that the results are not yet actionable. And so, there are noncovalently binding BTK inhibitors that are in development. At least 3 companies are studying such drugs right now, in clinical trials, that possibly could overcome resistance in these BTK mutations. I think it may be actionable in the future. Probably what it gives you now is a little bit of a lead time. The presence of these mutations have been found between 6 months and a year, let’s just say, to round it out, before patients have clinical progression. So if you detect a mutation, at least it gives you time, particularly for young, fit patients to start planning alternative strategies, other targeted agents, stem cell transplantation, or some alternative approach like a clinical trial, for example.

So we do check them in younger patients, sometimes sequentially. But if there’s a suspicion of resistance, then we check it when we think about switching patients. I think biologically you could argue maybe PI3K inhibitors would have a role in BTK-mutated patients, more so than in PLC-gamma-2. If they’re PLC-gamma-2 or BTK, you could argue for the use of BCL2 inhibitors. But I think we’re in the earliest stages of working out these precision medicine pathways based on specific mutations. I think it’s a couple years away.

Harry P. Erba, MD, PhD: That’s interesting. And then the drug that might be on the horizon—zanubrutinib?

Anthony R. Mato, MD, MSCE: This is a drug that’s really been studied, or at least has reported, in a limited number of patients with CLL. Like acalabrutinib, the early data appear to show it is well tolerated and active with response rates for both drugs exceeding 90%.

Transcript edited for clarity.

Harry P. Erba, MD, PhD: It is a little bit more complicated. There are other differences between chemotherapy and the BTK [Bruton tyrosine kinase] inhibitors. Let’s come back to that question when we get to toxicity profiles and comparing toxicities, like in the ECOG and the Alliance trials. Let’s move on to talking about the second approved BTK inhibitor, and that’s acalabrutinib.

Anthony R. Mato, MD, MSCE: Acalabrutinib is approved only for mantle cell lymphoma in the relapsed/refractory setting. It is not yet approved for CLL [chronic lymphocytic leukemia]. There have been registrational trials, which I hear are completed and may soon be reported on, but there is no indication for CLL just yet. It probably is used in a small proportion of patients off-label, maybe in ibrutinib-intolerant patients, specifically. But at this time, we don’t have any head-to-head data or any real-world data on acalabrutinib use in CLL.

Harry P. Erba, MD, PhD: What’s your experience been like in those ibrutinib-intolerant patients?

Anthony R. Mato, MD, MSCE: I’ve only used it a few times. I was part of the head-to-head trial versus ibrutinib, which has not yet reported. But I use it occasionally in some intolerant patients. For some patients, it’s a good answer. I think it may depend on the toxicity, but it’s limited in use so far.

Harry P. Erba, MD, PhD: Do you think there’s any reason to expect, or have you seen activity of acalabrutinib in patients who have been refractory or resistant to ibrutinib?

Anthony R. Mato, MD, MSCE: Probably not high expectations. You know, the resistance mechanisms to ibrutinib are still being worked out. There are C481S mutations in BTK, which if they’re affecting ibrutinib’s binding, should probably equally affect acalabrutinib’s binding. There are downstream mutations in PLC-gamma-2, which is downstream of BTK in the signaling pathway, which should be independent of both drugs. I think it’s still a bit of a black box. Although people originally thought that these 2 types of mutations represented all progressions, outside of transformation, it’s probably not the case.

Probably half of the progressions that we see do not have either mutation present. So it’s hard to know whether 1 drug would overcome it universally. But I think biologically there’s a low expectation for somebody who truly has ibrutinib resistance, that another covalently binding BTK inhibitor, either acalabrutinib or zanubrutinib, would overcome that.

Harry P. Erba, MD, PhD: OK. Do you think there’s a role for doing BTK mutational analysis? Do you do it?

Anthony R. Mato, MD, MSCE: I do think there is a role for it. I think it’s emerging. There are some centers where they check patients every 3 months. The problem is that the results are not yet actionable. And so, there are noncovalently binding BTK inhibitors that are in development. At least 3 companies are studying such drugs right now, in clinical trials, that possibly could overcome resistance in these BTK mutations. I think it may be actionable in the future. Probably what it gives you now is a little bit of a lead time. The presence of these mutations have been found between 6 months and a year, let’s just say, to round it out, before patients have clinical progression. So if you detect a mutation, at least it gives you time, particularly for young, fit patients to start planning alternative strategies, other targeted agents, stem cell transplantation, or some alternative approach like a clinical trial, for example.

So we do check them in younger patients, sometimes sequentially. But if there’s a suspicion of resistance, then we check it when we think about switching patients. I think biologically you could argue maybe PI3K inhibitors would have a role in BTK-mutated patients, more so than in PLC-gamma-2. If they’re PLC-gamma-2 or BTK, you could argue for the use of BCL2 inhibitors. But I think we’re in the earliest stages of working out these precision medicine pathways based on specific mutations. I think it’s a couple years away.

Harry P. Erba, MD, PhD: That’s interesting. And then the drug that might be on the horizon—zanubrutinib?

Anthony R. Mato, MD, MSCE: This is a drug that’s really been studied, or at least has reported, in a limited number of patients with CLL. Like acalabrutinib, the early data appear to show it is well tolerated and active with response rates for both drugs exceeding 90%.

Transcript edited for clarity.
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