Approved BTK Inhibitors for CLL

Ian Flinn, MD:Jan, I think you work with acalabrutinib a fair amount. Do you want to walk us through that a little bit?

Jan A. Burger, MD, PhD:Yeah. So both agents that are approved, ibrutinib and acalabrutinib for CLL [chronic lymphocytic leukemia]. Those are both covalent inhibitors, which means they form an irreversible bond to BTK [Bruton tyrosine kinase], to the activation site of BTK. So they have similarities in terms of their mechanism, how they bind to BTK, and how they inhibit BTK. But what you already said is that acalabrutinib, the second-generation molecule that is next in line now and is approved, is probably going to be used more frequently in the time to come. It is more selective for BTK and doesn’t have these off-target effects.

With that we could say, “Well, maybe it has advantages in terms of adverse effects.” Cross-trial comparisons are difficult, and therefore I don’t think we can definitively conclude that the newer-generation molecules are clearly better in terms of certain adverse effects. I think we need to wait for the randomized studies that are ongoing, comparing acalabrutinib with ibrutinib, to make a definitive conclusion about, for example, cardiac adverse effects. So mechanism of action is, to some extent, similar, but the newer-generation molecules are more selective.

The other distinction is that ibrutinib is given once a day. The second-generation molecules are given twice a day. I think that’s based on the idea that if you give it twice a day, maybe you have a little better occupancy of the target around the clock. But I think we already have a feeling that the efficacy of the molecules is very similar, so maybe that has some benefit in terms of adverse effects, in terms of efficacy. At least that’s my read of the data. I think the molecules are very similar. If you treat a CLL population, you can expect that the vast majority of patients are going to respond. Do you have a different take on that? It’s most likely going to come from the adverse effects, not so much from the efficacy.

Ian Flinn, MD:I agree completely with you. I think that it’s very hard. Most people think they’re going to work pretty well, pretty equally. There are large randomized trials going on. We wait for those results. But where there may be differences is in the adverse-effect profile. And you brought up some of the differences. Perhaps acalabrutinib may be a little more specific, but it is given twice a day versus once a day. And the thing that comes up, at least here in Tennessee a fair amount in our patient population, is that patients can’t be on a proton pump inhibitor. They can’t be on Protonix, a lot of my patients you need the acidic environment of the stomach more for the drug to be absorbed. So it’s not necessarily obvious to me that all patients should be on 1 or all should be on another. Perhaps they’re useful in different settings.

Transcript edited for clarity.