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New and Emerging BTK Inhibitors in Mantle Cell Lymphoma

Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Published: Thursday, Mar 28, 2019



Transcript: 

Brad S. Kahl, MD: Acalabrutinib has been a really nice addition to our management of mantle cell lymphoma. It received its FDA approval about a year and a half ago. It is pretty similar to ibrutinib. If you look at the efficacy data, there was a single-arm phase II clinical trial with over 100 patients. The overall response rate was better than 70%. The complete response rate might be a little higher than what we see with ibrutinib. It’s always difficult when you do cross-trial comparisons, but when you look at the 2 studies, there’s a suggestion that the complete response rate might be a little higher with acalabrutinib.

Acalabrutinib might be a little more active than ibrutinib in mantle cell lymphoma, although I would say the jury is still really out on that question. It also might be a little better-tolerated. There seems to be a little less arthralgia, a little less myalgia, a little less diarrhea, maybe a little less bleeding, and maybe a little less risk for atrial fibrillation. Notice that I’m qualifying all these with big maybes because these data sets are still in evolution, and I think we’re really still getting the safety and adverse-effect profile of these medicines established. I’m not yet ready to say definitively that acalabrutinib is more efficacious and better tolerated than ibrutinib. There are some head-to-head studies being done in CLL [chronic lymphocytic leukemia] that I think will really help clarify the safety and the adverse-effect profile of these medicines and how they stack up head to head.

Zanubrutinib is another BTK [Bruton tyrosine kinase] inhibitor, and it has some properties that may make it more selective. It is thought to be a more selective kinase inhibitor with fewer off-target effects and less effect on EGFR—so maybe fewer rashes and less diarrhea, and maybe fewer myalgias. It’s thought to have fewer effects on TEC, so maybe less bleeding. We really won’t know until we get large data sets with lots of patients treated. Only then will we know for sure whether it’s better tolerated.

It appears to have some pharmacodynamic properties, where it has very good uptake into lymph nodes. There is a thought and a hope that it might be an agent that is more efficacious in lymphomas where a lot of the disease is nodal. Again, this remains to be seen, and we need the studies to bear this out. But we saw some data presented at ASH [the American Society of Hematology Annual Meeting & Exposition] this year looking at zanubrutinib in mantle cell lymphoma in a study done in China. The response rates were very high, and interestingly, the complete response rate was higher than what we’ve seen with other BTK inhibitors. So there’s early evidence, a small amount of evidence that this might be a better BTK inhibitor. It might have some advantages over ibrutinib and maybe acalabrutinib, but it is too early to declare victory there yet. It’s going to require more study and more patients, but we’re hopeful that these studies with zanubrutinib and other BTK inhibitors pan out and we keep developing better and better BTK inhibitors as time goes on.

Transcript Edited for Clarity
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Transcript: 

Brad S. Kahl, MD: Acalabrutinib has been a really nice addition to our management of mantle cell lymphoma. It received its FDA approval about a year and a half ago. It is pretty similar to ibrutinib. If you look at the efficacy data, there was a single-arm phase II clinical trial with over 100 patients. The overall response rate was better than 70%. The complete response rate might be a little higher than what we see with ibrutinib. It’s always difficult when you do cross-trial comparisons, but when you look at the 2 studies, there’s a suggestion that the complete response rate might be a little higher with acalabrutinib.

Acalabrutinib might be a little more active than ibrutinib in mantle cell lymphoma, although I would say the jury is still really out on that question. It also might be a little better-tolerated. There seems to be a little less arthralgia, a little less myalgia, a little less diarrhea, maybe a little less bleeding, and maybe a little less risk for atrial fibrillation. Notice that I’m qualifying all these with big maybes because these data sets are still in evolution, and I think we’re really still getting the safety and adverse-effect profile of these medicines established. I’m not yet ready to say definitively that acalabrutinib is more efficacious and better tolerated than ibrutinib. There are some head-to-head studies being done in CLL [chronic lymphocytic leukemia] that I think will really help clarify the safety and the adverse-effect profile of these medicines and how they stack up head to head.

Zanubrutinib is another BTK [Bruton tyrosine kinase] inhibitor, and it has some properties that may make it more selective. It is thought to be a more selective kinase inhibitor with fewer off-target effects and less effect on EGFR—so maybe fewer rashes and less diarrhea, and maybe fewer myalgias. It’s thought to have fewer effects on TEC, so maybe less bleeding. We really won’t know until we get large data sets with lots of patients treated. Only then will we know for sure whether it’s better tolerated.

It appears to have some pharmacodynamic properties, where it has very good uptake into lymph nodes. There is a thought and a hope that it might be an agent that is more efficacious in lymphomas where a lot of the disease is nodal. Again, this remains to be seen, and we need the studies to bear this out. But we saw some data presented at ASH [the American Society of Hematology Annual Meeting & Exposition] this year looking at zanubrutinib in mantle cell lymphoma in a study done in China. The response rates were very high, and interestingly, the complete response rate was higher than what we’ve seen with other BTK inhibitors. So there’s early evidence, a small amount of evidence that this might be a better BTK inhibitor. It might have some advantages over ibrutinib and maybe acalabrutinib, but it is too early to declare victory there yet. It’s going to require more study and more patients, but we’re hopeful that these studies with zanubrutinib and other BTK inhibitors pan out and we keep developing better and better BTK inhibitors as time goes on.

Transcript Edited for Clarity
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