Dr Constantine Tam Discusses the Benefits of Zanubrutinib on Cardiac Effects

Compared with ibrutinib, zanubrutinib appears to have more of a benefit for patients with regards to less atrial fibrillation, hypertension, and other cardiac effects, explained Constantine S. Tam, MBBS, MD, clinical hematologist, Peter MacCallum Cancer Centre in Melbourne, Australia.

Transcript

Study results favor zanubrutinib for hypertension, for atrial fibrillation, for all those types of cardiac results, so are there certain populations that it would particularly benefit for them to take this drug over ibrutinib?

So, at the moment there’s not a whole lot of data about which patients get these kind of vascular side effects. Now for atrial fibrillation there is ibrutinib. There's a general feeling that older patients with hypertension and abnormal ECG [electrocardiogram], abnormal hearts, are the ones who get more atrial fibrillations, than those who don't. So, we didn't examine specifically in this study, you know whether the risk factors to event rates are pretty low anyway, but you extrapolate from this study that zanubrutinib causes less atrial fibrillation and less hypertension, which I can go into more detail about.

Then, one would say, “Well, those patients who potentially have a history of hypertension or have a history of atrial fibrillation, or have an abnormal ECG or abnormal echocardiogram, maybe they're the ones who would be better off on zanubrutinib compared to ibrutinib, because it's lower risk of a tribulation and worsening of hypertension.”

Is there something about the second-generation Bruton tyrosine kinase inhibitors that would tend to cause less of these cardiac effects?

We think is how clean the targeting is. So, you know, we don't really know what causes hypertension and atrial fibrillation. We look at congenital BTK [Bruton kinase tyrosine] deficiency—so these are humans born without BTK they don't really get atrial fibrillation or hypertension. So, presumably you can dispense with BTK and be okay from a kind of vascular point of view. So, we think that ibrutinib causes some of these side effects because it's not totally clean. So, it's like TEC, and EGFR [epidermal growth factor receptor], and JAK3 [Janus kinase 3], and a whole group of other enzymes, which are structurally related to BTK.

Now, neither zanubrutinib or alacabrutinib, you get less off-target enzyme inhibition. And I don't think anyone can actually put a hand on it and say this enzyme this causing it. But we just know that the cleaner it is, the better the profile.

And it's not just like hypertension, he fibrillation, a whole multitude of other side effects like muscle spasm, peripheral edema, pneumonitis, or pneumonia was reduced with zanubrutinib compared to ibrutinib. And I think a lot of the sudden pneumonia, were in fact pneumonitis. Because there's no real reason why there should be such a big difference in infective pneumonia.

Overall, the ability to stay on a drug longer seems to favor zanubrutinib. Is that a benefit of this drug over ibrutinib?

Correct, so the drug is easier to take. So, it's less side effects, less dose reduction, people can stay on it for longer. In terms of cumulative risk, so we actually examined the cumulative risk of atrial fibrillation and hypertension over time. And you see that for zanubrutinib, essentially, most of the events happen in the first 12 months and then it sort of plateaus. Whereas for ibrutinib we've seen it in an increasing cumulative pattern suggesting that you know, if you are going to take this drug for let's say 3 or 5 years. That zanubritinub may be a bit better because there's no cumulative effect on the vascular system, whereas ibrutinib appears to have one.