Dr Jennifer Brown: Zanubrutinib Efficacy Holds Up at ALPINE 39-Month Follow-Up in R/R CLL

Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia (CLL) Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, discussed the updated findings from the phase 3 ALPINE trial of zanubrutinib vs ibrutinib in CLL. Results from 39 months of follow-up were presented on Saturday at the American Society of Hematology Annual Meeting & Exposition.

Transcript

ALPINE results at 39 months show responses to zanubrutinib in CLL are sustained and deepened over time for most. How typical is it for patients with CLL or any hematological cancer to respond to a treatment this way?

When we first developed BTK [Bruton tyrosine kinase] inhibitors, I think we weren't necessarily expecting this type of response, but this is actually what we see with BTK-targeted inhibition. It's relatively slow in inducing response compared to something like chemotherapy, if the disease is sensitive to chemotherapy, but it continues to sustain and deepen the response over time and even over many years. So, this is actually typical of what we see with BTK inhibitors with CLL. In fact, we see deepening responses even in the control arm with ibrutinib, as we do with zanubrutinib—it's just that the response rate is higher, and the CR [complete response] rate is higher with the zanubrutinib than the ibrutinib.

Can you discuss the difference in responses among patients with 17p deletion with TP53 mutation?

That's our highest-risk subgroup of disease in CLL—patients who have p53 aberrant C, which is most commonly seen through deletion of the short arm of chromosome 17, but can also be seen through mutation. And most patients who have 17p deletion also have mutation of the other allele. These are the patients who are particularly poorly served historically by chemotherapy, so the development of the BTK inhibitors was particularly revolutionary for them. That's a group that we're always particularly interested in looking at the outcomes for, and that was a predefined subset in ALPINE.

In that group, we actually see an even bigger difference benefiting zanubrutinib compared to ibrutinib than we do in the overall population. And at this time point, we have 59% of patients still progression free on zanubrutinib compared to 41% with ibrutinib. So that's an 18% improvement in the progression-free survival at 39 months for this very-high-risk subgroup. I think the fact that we see an even bigger difference in this subgroup compared to the total population underscores the fact that it's likely a real efficacy difference that we're seeing driving the results of the trial, because this is the group where difference in efficacy should be most pronounced and most important. So, the fact that we're seeing it there, in particular, even more so than in the overall population, I think, is very convincing.

Relative to ibrutinib, patients taking zanubrutinib had fewer cardiac events and fewer serious cardiac events. Do we know how this translates into rates of hospitalization or costs to payers?

The only thing I can really comment on there is the ALPINE data. We did look into the rates of hospitalization at this follow-up for zanubrutinib vs ibrutinib, and it's actually a 10% lower rate. So, 46% of patients on the zanubrutinib arm were hospitalized for some reason over the course of the trial vs 56% for ibrutinib. I think that's a pretty significant difference, and the rate due to cardiac events was only about half—it was about 3% vs 7.5%. So, it looks like it's translating into benefits for the health care system as well.

What has been your experience in clinical practice with patients taking zanubrutinib relative to ibrutinib regarding the need for emergency room care or hospital admission?

My personal experience has been that those hospitalization rates I just told you sound really high to me, because I feel like our patients are actually rarely hospitalized on zanubrutinib. One thing you do see whenever you start any new CLL therapy, especially in the first 6 months, is that there's some tendency to get hospitalized for infections, which may be a little bit higher with the initiation of any therapy. But it tends to be similar across all treatments, and it improves over time as you get control of the disease.

If patients might be taking a BTK inhibitor for 3 years or even longer, do the differences in cardio safety results become even more important?

Absolutely, I think especially in terms of the atrial fibrillation and arrhythmia rates, because we know those are continually increasing and the cumulative incidence just goes up. So, that will just continue to be different over time. For the issue of ventricular arrhythmias, we didn't actually have any new events on either arm between the 2- and the 3-year follow-up. We don't really know what the timing of that is—that may tend to be a little bit earlier—although we did have several events in the latter part of the 2-year follow-up, and we need to continue to follow that to try and better understand that the timing of that. But, presumably, the time on the drugs is ongoing risk of cardiac events.

As patients with CLL contemplate taking a drug for 3 years or more, what side effects beyond cardiac effects become particularly difficult to live with over a long period that should be a consideration?

There are a number of side effects like that, which are typically much more common with ibrutinib than with zanubrutinib. So, things like rashes—some of which can be very difficult to control—things like joint aches and pains, muscle aches and pains, can actually be quite persistent. Fatigue related to the drug is actually something we also see with ibrutinib. And, you know, people can tolerate it for 6 months or even a year, but then you're getting to 3 and 4 years, it's forever. So, that can be an issue as well.

Many of these might not reach grade 3 or higher by clinical trial criteria, but they're grade 1 or 2, and they go on forever. Another one is diarrhea, actually, low-grade diarrhea with ibrutinib that's much less with the zanubrutinib. All of those can kind of accumulate, and I think this is why, especially in ibrutinib trials, we tend to see patients going off as you get to 3, 4, 5, and 6 years. I think that's going to be much less true with zanubrutinib because many of my patients on zabubrutinib tell me they don't even know they're taking anything. Now, that's usually fairly soon after they start, but it still tends to stay similar.