Recent Approval of Zanubrutinib for R/R MCL

Transcript: Ian Flinn, MD: That takes us to some of the more recent targeted therapies. We’re going to talk a bit about BTK [Bruton tyrosine kinase] inhibitors. The newest kid on the block is zanubrutinib. I guess you would call it a second-generation BTK inhibitor. It is thought to be more selective in terms of not hitting as many off-target kinases as some of the other drugs in its class. The hope is that by being more selective, you’re not going to have some of the off-target toxicities, such as bleeding, cardiac effects, diarrhea, rash, and other potential problems.

We don’t have as much experience in the United States because a lot of the development was done ex-US. There were 2 different pivotal trial that led to the approval. One was done predominantly within China, and the other was done outside of China. Both showed very good remission rates, durable remissions, which were as good or better than what we had seen in other single-arm, phase II trials that were conducted with some of the other BTK inhibitors. It seems like an interesting drug, and we’ll have to see how that ultimately plays out.

Bijal, have you had any experience with it yet? What’s your take on the data?

Bijal Shah, MD: I think the data are very good. It’s important to understand when we’re trying to dissect these cross-trial comparisons, who are the patients coming on to the study? Where are they in their treatment course? When ACALA [acalabrutinib] first came on the market, we already knew BTKs were working. We were already excited by what we were seeing with ibrutinib. Of course, now that we have an acalabrutinib trial in our hands, we want to get them on that trial as soon as we can, so we’re not waiting until third or fourth or fifth line. That also goes for community referrals. They’re sending them to us earlier. Before giving them R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone], bendamustine, Rituxan [rituximab]—fill in the blank, your next chemotherapy regimen—they’re coming to us now for the acalabrutinib study.

I think this is also something that we’re seeing in the zanubrutinib study. Patients are coming in earlier, they’re not quite as beaten up, and they have a disease that may be a bit more sensitive to BTKs at that point.

I do think that’s an important thing to keep in mind as we’re doing these cross-trial comparisons. With that said, it looks to be an effective BTK, and that’s also an important observation, because now, we’re going to have 3 in the field. We’re really going to spend a lot of time trying to dissect which BTK is best for which patient.

Ian Flinn, MD: We’ve used it in clinical trials outside of the mantle cell lymphoma group, and it seems to be effective and relatively easy to use. There are data that say that there is very high occupancy of the BTK when given in the doses that have been approved. There are also some data that suggest that you get BTK occupancy within biopsy specimens of patients with lymphoma. Is that enough to make you want to use it? What are you going to do?

Tycel Jovelle Phillips, MD: My experience is the same as yours, just clinical trial experience. By the time we were asked to participate in the trial, most of our patients were treatment-naïve. Tolerability seems good so far, but again, it’s early. Ibrutinib was also very good in the beginning before some of these long-term adverse effects had come up. I think, as Bijal said, this is a very exciting time. We have 3 different drugs, but I think time is really the only determinant here to help us tease out the differences between the 3. They all appear to be effective.

Looking at the data, as was pointed out, acalabrutinib and zanubrutinib were all in first relapse for most of the patients, whereas the ibrutinib population was a bit more heavily pretreated, based on the response criteria. It’s kind of hard to gauge it head-to-head, but I think overall, none of us really feel that, at least efficacy-wise, 1 is better than other. It will come to dosing, whether you want to do once daily or twice daily. Zanubrutinib gives you a little more flexibility, but tolerability is important. Because these are agents patients will be on for quite a bit of time, they have to be able to tolerate the medications and actually adhere to taking the medications.

Ian Flinn, MD: You bring up an interesting point that zanubrutinib is approved for 2 different—what is it, 160 mg twice a day versus 320 mg once a day? I think in most of the studies, it is twice a day. If you prescribed it, would you use the twice a day or once a day? The twice a day is based on trying to maximize occupancy, so what do you think?

Tycel Jovelle Phillips, MD: I think it really depends on the patient and if I can trust them to take a pill twice a day. If it’s a single man, probably not.

Seriously, it’s really about comfort level as far as your patient’s compliance. I’m sure they went with a once-a-day testing just because some patients will never remember to take that second pill. I’ve heard that argument from people with ACALA [acalabrutinib] versus ibrutinib. They don’t trust the patient to take the second pill. I agree with you. I think it’s important they designed it as twice a day for the continued occupancy, so I would hopefully try to do twice-a-day dosing. Very rarely would I try once-a-day dosing.

Ian Flinn, MD: I don’t think your comments are trivial at all about the ability to take it twice per day. I know that once I get on antibiotics or something, I can hardly remember to take the medication the second time after the third day. It’s amazing that patients can be as compliant as they are.

Javier, we need you to weigh in on this. What do you think of the zanubrutinib data and its comparison to ibrutinib, in terms of the [adverse] effect profile?

Javier Munoz, MD, FACP: As you said, there were 2 studies. The 1 made in China, and the 1 that was an international study, and we were part of the study, so we had experience with zanubrutinib, when it comes to the trials. After the FDA approval, we have prescribed it in 1 patient. We have N-of-1 experience after the approval.

To answer your previous question, interestingly, I also debated with the patient about whether he would take it once per day or twice per day. I assumed he might prefer once, but I was ready to have the discussion about why twice per day could also be reasonable. Interestingly, he decided to go with twice-per-day dosing for himself. The reason is that he takes other medications, and he is used to taking medications in the morning before going to work and in the afternoon after he comes back to work. He actually volunteered to take twice per day. That’s something interesting that I have seen after the FDA approval. Zanubrutinib is definitely part of the crescendo of development when it comes to BTK inhibitors. We are trying to hit that sweet spot of higher efficacy and lower toxicity, but we do not know if that is accurate at this point. We need randomized clinical trials to answer those questions. We need time and we need the data.

Ian Flinn, MD: You bring up a good point that there is a randomized clinical trial that is being conducted, although it’s in a different disease. It’s in CLL [chronic lymphocytic leukemia]. I think I would be comfortable with extrapolating the adverse event profile from 1 disease to the next. How about you, Tycel?

Tycel Jovelle Phillips, MD: I agree. Obviously, the CLL patients will be exposed to those drugs for a lot longer than we’re used to. If it hasn’t shown up in that patient population, it’s likely not to show up in our patients, either. I don’t think we need to recapitulate that same trial.

Transcript Edited for Clarity