Bruton’s Tyrosine Kinase in B-Cell Malignancies: Advances in Targeted Therapy - Episode 6

Zanubrutinib for B-Cell Lymphomas

Drs Shadman and Cohen review clinical trials of zanubrutinib in B-cell lymphomas.

Mazyar Shadman, MD, MPH: Moving on to zanubrutinib, that’s another second-generation BTK [Bruton tyrosine kinase] inhibitor with the same mechanism of action. It first was approved for mantle cell lymphoma, and is another effective drug. For differences, the common question is whether to use ACALA [acalabrutinib] or ZANU [zanubrutinib]. Again, we talked about the fact that in the absence of head-to-head trials, to me it’s impossible to make a comment about that. Logistically at least, the PPI issue, proton pump inhibitor, and limitations with acalabrutinib could be a problem in some patients, with the fact that zanubrutinib could be given as once-a-day dosing. But both are great drugs, and it’s extremely hard to pick one over the other, a great experience with both drugs.

Zanubrutinib for mantle cell lymphoma, it has been approved. It’s the only FDA indication at the moment for zanubrutinib, although we’ll talk about some of the CLL [chronic lymphocytic leukemia] studies. We recently had the 3-year follow-up for mantle cell presented at the EHA [European Hematology Association] meeting. I’ll start by saying there was a high overall response rate of more than 80%, and actually a very high CR [complete response] rate with zanubrutinib. We’re not used to seeing a lot of high CR rates in CLL with BTK inhibitors. Is that surprising to you to see that kind of CR in mantle cell, in the range of 70%?

Jonathon Cohen, MD, MS: It’s very promising. It makes me wonder a little bit. You had pointed out that some of the initial studies of ibrutinib were done using some different criteria. But we know that ibrutinib had a CR rate of around 20% or so in some of the initial relapsed mantle cell studies. It certainly is an improvement over that. Again, we’ll have to see with time if that ultimately translates into a duration of response benefit. But it’s clear that zanubrutinib is a very highly effective therapy. As you point out, we have a number of studies now that have compared it at least head-to-head to ibrutinib that suggest that there is a toxicity benefit as well, similar to what we saw with acalabrutinib. Where it will be challenging is if you must make a decision between acalabrutinib and zanubrutinib, as you point out, there’s not necessarily a clear toxicity difference. Perhaps acalabrutinib is more associated with headaches. We have the PPI question, but in general, they’re both very well tolerated therapies.

Mazyar Shadman, MD, MPH: The 3-year PFS [progression-free survival] they reported at the EHA meeting from zanubrutinib monotherapy in mantle cell was 47.6%. I’m looking at it right now. It’s a pretty good PFS. The PK [pharmacokinetics] data from zanubrutinib initially were very interesting in the BTK occupancy. It sounds like the clinical data are supporting the efficacy of this drug. We keep repeating that we can’t compare between the drugs in the absence of a clinical trial. These are really indirect conclusions we’re making from individual studies.

We talked about the fact that zanubrutinib now is approved for mantle cell lymphoma, but there are a number of studies for zanubrutinib in the CLL population. Most likely we will see this drug approved, again just looking at the studies for CLL. When we look at CLL, the 17p deletion population is kind of treated differently, and there are now published follow-up data from monotherapy zanubrutinib in patients with 17p in the frontline setting. It was more than 100 patients, published with an 18-month PFS of I believe around 80%-plus. It’s great, it’s consistent with what we saw with ibrutinib, and there are less data for acalabrutinib for 17p in the front line. But clearly the drug has activity and is, as we talked about, is well tolerated.

Now, the head-to-head trial comparing bendamustine/rituximab to zanubrutinib monotherapy, we just heard about the press release that it met the primary end point of PFS. We haven’t seen any data. We’ll wait for that.

This transcript has been edited for clarity.