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CLL and MCL: Factors in Selecting a BTK Inhibitor


Homing in on specific Bruton tyrosine kinase inhibitors used to treat B-cell malignancies, an expert considers selecting one agent over another.


Michael A. Kolodziej, MD: Ibrutinib has been around for several years now. There’s a lot of clinical experience with it. Acalabrutinib has been around a year and change. Zanubrutinib just got approved for mantle cell lymphoma. I think we’ll see Waldenström macroglobulinemia soon to follow, we’ll see chronic lymphocytic leukemia [CLL] to follow after that, probably within the next year or year-and-a-half. So we will see some uniformity in terms of the Bruton tyrosine kinase [BTK] inhibitor label indications. There will be subtle differences. The preclinical information on zanubrutinib is very interesting because it really does have a longer plasma half-life and block the enzyme more effectively. Again, we’ll have to wait and see. It does appear to have less toxicity in the limited data that are out. I would say that’s attractive in general.

But the challenge that we have as clinicians and the challenge that we have as payers is that things are happening so fast. We probably won’t have a real good handle on the benefits of the second-generation BTK inhibitors. And keep in mind there’s a third generation that’s about to hit. There are at least 2 drugs that are close to making it to meaningful clinical trials. And those drugs may actually work even when patients are ibrutinib-resistant, so again, very interesting.

I would be remiss not to talk a little bit about cost. Ibrutinib and zanubrutinib are pretty much the same. Acalabrutinib is a little bit more expensive, 8% or 10% more expensive, something like that. We shall see what happens with the cost over time. As we discussed earlier, if you’re in a payer’s seat and you’ve got these three drugs and they all work pretty much the same and they cost, give or take, $150,000 a year—because that’s what they cost, give or take $150,000 a year—there’s a temptation to start thinking about, let’s make a deal. Because if you can show comparable efficacy and comparable toxicity profiles, then because they’re oral drugs the ability to manage access through innovative contracting is really an attractive thought.

I mention oral agents because, of course, intravenous drugs are much more complicated because of ASPs and all that other stuff. Oral drugs are the area where we will most likely see—at least initially, in my opinion—more innovative contracting models because you don’t have to worry about ASPs. If, over time, however, the second-generation drugs wind up having a more favorable toxicity profile, it makes it a little bit harder to be innovative in the contracting universe. We’ll have to wait and see.

So the issue with dosing, we’ll see whether it matters. It either matters or it doesn’t matter. What do I mean by that? So, when you think about dosing, there’s a couple of things. Number 1 is adherence. So you want to make sure that you optimize adherence, and this is not unique to this class of drugs. This is true across the spectrum of oral cancer drugs, and oral cancer drugs are a third of cancer drugs so it’s a big deal.

You want to make it convenient for the patient. And second of all, you want to make it easy to modify the dose in the event of toxicity. And that’s really important because of waste. So, if you’ve got a limited number of dosing opportunities—pill size, or capsule size—and you have to modify the dose, if you have to throw away that prescription, that’s like throwing away $10,000. That’s not so grand. So the advantage of being flexible in dosing from a payer and a physician and a patient perspective are No. 1. Does it make it easier for me to be compliant? And No. 2 Do the dosing formulas make it easy for me to modify the regimen and maintain efficacy, while being able to adapt to toxicity and avoid waste? Because boy, the payers hate waste with these specialty drugs. They hate it so much.

It’s early days, and we’ve got a lot to learn about the differences between these drugs. There are a couple of theoretical differences that may be important. We talked briefly about ibrutinib and bleeding risk, and that’s a big deal because these people are old and they’re on anticoagulants, and you don’t want to give ibrutinib to somebody on anticoagulants. On the other hand, these novel agents, both acalabrutinib and zanubrutinib, don’t have the bleeding risk. It’s a fraction. And so they may be better choices.

The other thing that seems to be true, especially for zanubrutinib, there’s less drug interactions. All these patients are immunosuppressed, 100% of them. If you need to give somebody fluconazole, that’s a big deal. But with zanubrutinib, it doesn’t appear to be a big deal. So that may wind up being important because of the fact that these patients all have comorbidities. But it’s, in my opinion, it’s a little bit premature to say this is going to be a distinguishing characteristic. At this point, I suspect what will happen is as the Food and Drug Administration [FDA] label indications of zanubrutinib catches up to the other 2 physicians will choose one or the other based on bleeding risk, drug interactions, and stuff like that. And then ultimately, we’ll figure out the truth.

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