Patient Selection Among FDA Approved BTK Inhibitors

Transcript: Michael Wang, MD: The dosing difference among the 3 BTK [Bruton tyrosine kinase] inhibitors is that ibrutinib is a once-a-day drug, acalabrutinib is a twice-a-day drug, and zanubrutinib is a twice-a-day drug. The targeted occupancy among the 3 is very good. For their profile, they achieved a 95% to 99% of a target occupancy with a time elapse. I really think that the bid [twice a day] dosing and once-a-day dosing based on a targeted occupancy are similar. But a lot of people in the industry and the pharmaceutical drug development area, they think that a twice-a-day drug is better than once-a-day drug in terms of target occupancy and a constant occupancy of the targets.

While I’m not an expert on that, I think the target occupancy is very high. I’m not able to see the difference between target occupancy from once-a-day drugs to twice-a-day drugs like acalabrutinib and zanubrutinib. But I think the strategy to try to use a twice-a-day dosing in an attempt to occupy the target more consistently and with higher occupancy than they can achieve is a welcome strategy.

If you use a once-a-day drug if the patient has adverse effects that are too severe, you have to go down for them, ibrutinib from 560 mg to 420 mg and then to 280 mg and to 140 mg gradually, right? But for zanubrutinib and acalabrutinib, the first step—if the toxicity is too much—is you would cut the dose by half by changing it to a once-a-day drug. That’s 1 way to do it. Another way to do it, instead of changing dramatically from 2 times per day to 1 time per day, you can also cut the dose in half and still make it 2 times a day. This is the flexibility of the dose scheduling. These are subjective estimations. We do not have any data to support whether changing from twice a day to once a day or cut down the dose interval to maintain twice a day is equal. We don’t have data to see that. But a twice-a-day drug is more flexible than a once-a-day drug in terms of dose adjustment and schedule adjustment.

A lot of community doctors will likely use the newest BTK inhibitors. They think the newest ones may be the best ones. That’s the impression. A lot of people want to use the newest one. On the other side, a lot of people are used to the older inhibitors. They already developed the habits. They already know how to get the drug from the special pharmacy. They will not change. So, it is very hard for me to guess what the community doctors will do. But what I would do is consider the different adverse-effect profiles.

For example, if I have a patient with heart problems—they have dilated cardiomyopathy, a history of atrial fibrillation, a cardiac CABG [coronary artery bypass grafting], stents—I probably would start with zanubrutinib or acalabrutinib. So far the reported atrial fibrillation rate is low, but in the future maybe we’ll prove the problems to be the same with more cases treated, more follow-up. For now, it appears that it’s less cardiotoxic. If I give the new drug the benefit of the doubt, for cardiac cases I would use the newest inhibitors.

In terms of infection, the same thing. If the patient has a smoking history, they have a lot of pneumonia, they keep having COPD [chronic obstructive pulmonary disease] like chronic smoker’s lung, I probably would start with the newest BTK inhibitors. That’s another thing that maybe will be proven to be similar—the infections—but at least for now they appear to be less toxic in terms of infections. Let’s say a young patient has migraine headaches, I would never use acalabrutinib because acalabrutinib is the only BTK inhibitor that would consistently induce a headache. I would not use it because of the headaches. If the patient has migraine, ...I would not. If the patient has a history of stroke, I may stay away from acalabrutinib and use zanubrutinib.

Zanubrutinib is a very effective drug so far, an 84% response rate in the 2 prior lines of therapy. I have performed the clinical trials, so I would try to use it. It’s not quite available. The drug is approved, and we have to get it on the formulary at The University of Texas MD Anderson Cancer Center before we can use it. We’re trying to see if we can get on the formulary, so a lot of detailed steps to use the drug. I think the community is used to ibrutinib and acalabrutinib, and there’s a delayed lag before the community would start using it. I think zanubrutinib will be widely used in the Asian countries, less used in the Western world. It also depends on the marketing force, the strategy. It depends on where the companies’ strategies are to use the drug, in which population. There are lots of other factors to influence it.

Transcript Edited for Clarity