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Differentiating BTK Inhibitor Mechanisms of Action in MCL

Panelists: Charu Aggarwal, MD, MPH, Hospital of the University of Pennsylvania; Hossein Borghaei, DO, Fox Chase Cancer Center; H. Jack West, MD, Swedish Cancer Institute
Published: Wednesday, Feb 13, 2019



Transcript: 

Bijal D. Shah, MD: When we talk about ibrutinib and acalabrutinib, it’s important to understand that their primary mechanism of action is the inhibition of BTK. When we talk about how the 2 agents differ, it does appear that acalabrutinib is more selective for BTK, whereas we can see some other, more in the way of off-target effects with ibrutinib. How much that plays into benefit and how much that plays into toxicity are still unknowns. Again, we just need to follow patients with acalabrutinib longer and generate the follow-up data. And if it looks like truly this is a better-tolerated agent, then great, that’s a wonderful thing to be able to take to patients.

Alternatively, as I mentioned, if they turn out to be very similar in terms of atrial dysrhythmias, in terms of bruising or bruisability and the like, then I think we just have to take a step back and maybe agree that there may not be much of a difference. Listen to what I’m saying: That’s OK, and I think that’s the take-home message. If they turn out to be similar in benefit and risk, guess who wins. Because now with one insurer or one pharmacy group or benefit manager—I apologize if I’m butchering their names—the patients are going to get a cheaper drug from one group versus another, and that’s good. We need competition. Competition isn’t going to hurt anyone. It’s just going to push, honestly, both companies to develop their drugs in novel ways and to try to price their drugs in ways that patients can better afford.

Eduardo Sotomayor, MD: Acalabrutinib is a more specific BTK inhibitor, as compared with ibrutinib. The studies of 12 months’ follow-up with acalabrutinib were presented at ASH [American Society of Hematology Annual Meeting & Exposition] last year, and this was updated this year. So the overall response rate and the complete response rate are initially—although you need to do a head-to-head comparison—exciting because we are seeing better overall response rates, better complete response rates, and fewer adverse effects. That was last year. But to tell you the truth, I think we need to wait and see 2 or 3 or 4 years’ follow-up in order to say because it’s more specific versus acalabrutinib, perhaps it’s more potent, perhaps it’s associated with fewer adverse effects.

So I think that it’s a good drug, but in order for any of us to say one is better than the other, I think we need to wait. For instance, in the update of the acalabrutinib data in 2018, we start to see episodes of hemorrhage, episodes of bleeding. There is no report of atrial fibrillation, but there is report of other cardiac events in the follow-up. Again, as the data mature, then we’re going to be able to say, “So what are the differences or not between the ibrutinib, acalabrutinib, and also other types of Bruton tyrosine kinases that are being assessed?”

Zanubrutinib is an interesting BTK inhibitor that is more potent compared with the other BTK inhibitors. So you heard my comments about acalabrutinib with 2 years’ follow-up presentation. I think this drug is still in earlier development. Now, there were 2 presentations at ASH, so one clinical trial conducted in China and the other one, a global clinical trial in which we see very good overall response rate, very good CR [complete response] rate. I think in terms of safety, we are seeing similar adverse effects compared with the others. Although it’s still early to say, but there seems to be more incidence of some pulmonary events with this new class of BTK inhibitor.

So I would summarize by saying, yes, we are excited, but we need long-term follow-up data in order to say where this drug will play a role in the management of patients with mantle cell lymphoma. Also, we need to be aware that sometimes more potent doesn’t mean better. So yes, more potent in killing the B cells, but I want to emphasize again, most of these patients are elderly populations, and therefore, if we’re going to use a potent drug that we all get excited about, we need to look at the safety profile.

In terms of mechanism of action, what we know is that zanubrutinib seems to be mostly engaged with an enzyme for a prolonged period of time. What we call high occupancy rate and also high levels in the lymph nodes are seen with zanubrutinib as compared with ibrutinib.

Transcript Edited for Clarity 
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Transcript: 

Bijal D. Shah, MD: When we talk about ibrutinib and acalabrutinib, it’s important to understand that their primary mechanism of action is the inhibition of BTK. When we talk about how the 2 agents differ, it does appear that acalabrutinib is more selective for BTK, whereas we can see some other, more in the way of off-target effects with ibrutinib. How much that plays into benefit and how much that plays into toxicity are still unknowns. Again, we just need to follow patients with acalabrutinib longer and generate the follow-up data. And if it looks like truly this is a better-tolerated agent, then great, that’s a wonderful thing to be able to take to patients.

Alternatively, as I mentioned, if they turn out to be very similar in terms of atrial dysrhythmias, in terms of bruising or bruisability and the like, then I think we just have to take a step back and maybe agree that there may not be much of a difference. Listen to what I’m saying: That’s OK, and I think that’s the take-home message. If they turn out to be similar in benefit and risk, guess who wins. Because now with one insurer or one pharmacy group or benefit manager—I apologize if I’m butchering their names—the patients are going to get a cheaper drug from one group versus another, and that’s good. We need competition. Competition isn’t going to hurt anyone. It’s just going to push, honestly, both companies to develop their drugs in novel ways and to try to price their drugs in ways that patients can better afford.

Eduardo Sotomayor, MD: Acalabrutinib is a more specific BTK inhibitor, as compared with ibrutinib. The studies of 12 months’ follow-up with acalabrutinib were presented at ASH [American Society of Hematology Annual Meeting & Exposition] last year, and this was updated this year. So the overall response rate and the complete response rate are initially—although you need to do a head-to-head comparison—exciting because we are seeing better overall response rates, better complete response rates, and fewer adverse effects. That was last year. But to tell you the truth, I think we need to wait and see 2 or 3 or 4 years’ follow-up in order to say because it’s more specific versus acalabrutinib, perhaps it’s more potent, perhaps it’s associated with fewer adverse effects.

So I think that it’s a good drug, but in order for any of us to say one is better than the other, I think we need to wait. For instance, in the update of the acalabrutinib data in 2018, we start to see episodes of hemorrhage, episodes of bleeding. There is no report of atrial fibrillation, but there is report of other cardiac events in the follow-up. Again, as the data mature, then we’re going to be able to say, “So what are the differences or not between the ibrutinib, acalabrutinib, and also other types of Bruton tyrosine kinases that are being assessed?”

Zanubrutinib is an interesting BTK inhibitor that is more potent compared with the other BTK inhibitors. So you heard my comments about acalabrutinib with 2 years’ follow-up presentation. I think this drug is still in earlier development. Now, there were 2 presentations at ASH, so one clinical trial conducted in China and the other one, a global clinical trial in which we see very good overall response rate, very good CR [complete response] rate. I think in terms of safety, we are seeing similar adverse effects compared with the others. Although it’s still early to say, but there seems to be more incidence of some pulmonary events with this new class of BTK inhibitor.

So I would summarize by saying, yes, we are excited, but we need long-term follow-up data in order to say where this drug will play a role in the management of patients with mantle cell lymphoma. Also, we need to be aware that sometimes more potent doesn’t mean better. So yes, more potent in killing the B cells, but I want to emphasize again, most of these patients are elderly populations, and therefore, if we’re going to use a potent drug that we all get excited about, we need to look at the safety profile.

In terms of mechanism of action, what we know is that zanubrutinib seems to be mostly engaged with an enzyme for a prolonged period of time. What we call high occupancy rate and also high levels in the lymph nodes are seen with zanubrutinib as compared with ibrutinib.

Transcript Edited for Clarity 
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