Selecting the Appropriate BTKi in MCL and Potential Role of Pirtobrutinib


A detailed look at how to select the appropriate BTK inhibitor to treat patients with MCL and the potential role of the non-covalent BTK inhibitor pirtobrutinib in MCL.


Alexey V. Danilov, MD, PhD: Bijal, you published exciting analysis of real-world treatment patterns in MCL [mantle cell lymphoma] with BTK [Bruton tyrosine kinase] inhibitors. Could you walk us through it a bit?

Bijal D. Shah, MD: Yes. This was a project we did with Cardinal Health, and we wanted to try to better understand how they were being used, when they were being used, and whether there were features that would predict for benefit, or lack thereof. We couldn’t see a clear statistical benefit in terms of efficacy for one BTK inhibitor vs another. They were all similar in that regard. There were certain features, as you might suspect, that come with lack of benefits. So patients who present with higher burden disease, as you might guess, are going to derive less of a benefit.

One of the things I was pleased to see was use in an earlier line of setting, and because this is the real world, we compared frontline vs second line and beyond. When it was used earlier, it had better outcomes associated with it. This is perhaps as expected, but it was nice to be reassured of that. We’ve done other analyses using different data sets, getting at what we were talking about, the difference between different BTK inhibitors and trying to understand the settings in which they’re used, and it is a bit interesting to see these drugs used in settings where it might not be ideal. You were talking about having to dose reduce acalabrutinib, for example, and the person is on a PPI [proton pump inhibitor], they’re not going to be getting effective exposure to the drug. Now there’s a new tablet formulation that will fix that. But it is to say that these are things that surprised us in the data analyses. And it wasn’t just that, looking at folks with a prior history of atrial fibrillation, and so on.

Alexey V. Danilov, MD, PhD: Yes, all drugs we use are associated with toxicities, and BTK inhibitors are not an exception. We all worry about atrial fibrillation. The rates are different between those 3 drugs, it seems. But patients who are older, patients who have a history of A-fib [atrial fibrillation] are at particularly high risk. Then we worry about hypertension, other major adverse cardiovascular events, which have been shown to occur both with ibrutinib and acalabrutinib. The Ohio State [University] published a series on both. There are quite a few of these nuisance adverse events, [such as] headache for acalabrutinib, fatigue, arthralgias with essentially all of them. How much hypertension do you see in the clinic with these agents, Boyu?

Boyu Hu, MD: Yes, I see quite a bit. It was more so with ibrutinib. Every time a patient comes in on a BTK inhibitor, their blood pressure is sometimes a bit higher than it was at baseline, maybe because they’re coming to see me for the day. It’s probably around a quarter of my patients who will develop some hypertension. And that’s what the data have shown, that the longer you’re on it, it doesn’t matter if you’ve been on it for only 1 year vs 5 or 5-plus years, hypertension still continues to be an issue even if you’re on it for a long time.

Alexey V. Danilov, MD, PhD: What’s your first reflex? Do you dose reduce, or do you escalate antihypertensive therapy?

Boyu Hu, MD: I escalate antihypertensive therapies. There are good drugs that don’t interact with BTK inhibitors that control hypertension quite well. I’ll do that first before I de-escalate. Now, if they are really high, you may want to drug hold for a few days to make sure they’re not having hypertensive emergency. But outside of that, I will definitely escalate antihypertensives first.

Alexey V. Danilov, MD, PhD: All right. Bijal, you already mentioned pirtobrutinib, that you’re excited about that. And our patient in this first case is experiencing a response to this drug. Recently at this ASH [American Society of Hematology annual meeting], we had an update on the BRUIN study both in CLL [chronic lymphocytic leukemia] and MCL. Matt, can you tell us about it?

Matthew J. Matasar, MD: To frame the conversation, pirtobrutinib is a drug that’s in development in mantle cell lymphoma as well as other B-cell lymphomas. The commercially available BTK inhibitors are covalent binding BTK agents, and they all share that mechanism of action. This is a noncovalent BTK inhibitor that has been shown in early clinical work to be active in mantle cell lymphoma as well as other B-cell lymphomas in patients who have been refractory to or intolerant of covalent BTK inhibitors. The updates here at ASH affirm our understanding that indeed, pirtobrutinib is active in mantle cell lymphoma, with good response rates of about 60%. And we’re starting to see some measure of durability of those responses. Certainly pirtobrutinib is not curative therapy, but active and some measure of durability. The toxicity profile has been unchanged, with no clear signal of late emerging adverse effects, low rates of our BTK bugaboos of A-fib and bleeding. It clarifies and adds to our understanding that pirtobrutinib is a promising agent in this field.

Alexey V. Danilov, MD, PhD: Yes, and Bijal already mentioned too, there are clinical trials that are making an attempt to move pirtobrutinib into earlier lines of therapy. For example, MCL-321, which randomizes pirtobrutinib against the covalent BTK inhibitors. Are you also excited to use it in earlier lines of therapy?

Matthew J. Matasar, MD: My challenge with this is analogous to our discussion of the SHINE study. What I’ve said to others is that I worry that Loxo [Oncology], the company that makes pirtobrutinib, is a victim of their own success. They’ve shown that their drug is very effective in a patient population for which we have relatively fewer options, BTK refractory patients. I’m comfortable in a future state imagining treating such patients with pirtobrutinib. We don’t know the other. I don’t know if I can offer covalent BTK inhibitors to patients after they’ve progressed on or been intolerant to pirtobrutinib. Even if pirtobrutinib manages to beat ibrutinib in head-to-head battle, it doesn’t get at the question of sequence. I don’t know whether a patient is better served by starting with a covalent BTK inhibitor followed by pirtobrutinib vs beginning with pirtobrutinib and then going into the void.

Alexey V. Danilov, MD, PhD: Yes, and pirtobrutinib is not the only noncovalent BTK inhibitor in development; nemtabrutinib is another example. Again, this is a rapidly evolving field, and we will have more data.

Transcript edited for clarity.

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