Bruton’s Tyrosine Kinase in B-Cell Malignancies: Advances in Targeted Therapy - Episode 7


Two experts discuss use of ibrutinib and zanubrutinib and data from the ALPINE and ELEVATE-RR trials.

Mazyar Shadman, MD, MPH: We have the recently presented ALPINE study, which is head-to-head, 1:1 randomization between zanubrutinib and ibrutinib in patients with relapsed/refractory CLL [chronic lymphocytic leukemia]. Should we talk about the ALPINE study? It was presented at the EHA [European Hematology Association] meeting just a couple of months ago. What do you think about ALPINE, and how is it different from ELEVATE-RR? That’s a common question we’re getting every day.

Jonathon Cohen, MD, MS: It’s a good question, and basically we see that similarly to what we saw with the ELEVATE trial, that zanubrutinib has a very favorable toxicity profile. Once zanubrutinib ultimately becomes approved for CLL, I suspect it’s going to be used quite commonly. It’s very effective and like you said, we’ll see as we get more data in comparison to BR [bendamustine and rituximab] as well. I was curious, what were your thoughts about it? It’s clearly a well-tolerated agent that’s highly effective. I’m not sure if it’s going to answer the question that you brought up before about whether one sort of second-generation BTK [Bruton tyrosine kinase] inhibitor is superior to the other from the standpoint of tolerability.

Mazyar Shadman, MD, MPH: Absolutely. I don’t think we can answer that question. We can talk probably about the 2 studies and how they’re different. We talked about ELEVATE a few minutes ago. ALPINE is a similar design, obviously head-to-head randomized. First, it included all-comers, not necessarily high-risk 17p or 11q deletions. The primary end point was noninferiority in overall response, CR [complete response] and PR [partial response]. PRL [partial response with lymphocytosis] was not part of that definition, apparently because of what the FDA mandated based on the question that was asked from the presenter at the EHA meeting. I mention that because it’s a common question why not PRL because we know that PRL is considered like a PR in CLL. For whatever reason, the primary end point was overall response, CR and PR, and noninferiority and superiority. And the study did show superiority of zanubrutinib over ibrutinib for that primary end point.

It should be noted that follow-up between the 2 studies was very different. ELEVATE had a 45-month follow-up versus 15 months for the ALPINE study. But with the short follow-up, the PFS [progression-free survival], at least the curves when you look at them, they also look separated. Now, this is something for which we would need to look at the longer follow-up. The PFS curves over time are more meaningful than the short follow-up. But at least it is not inferior to ibrutinib. And there are some signals that maybe we’re seeing a higher efficacy, and the study did meet the primary end point for that, so the PFS we’ll continue to watch. Also, the safety profile overall, when you look, the family of specific AEs [adverse events] were basically better with zanubrutinib. There was a higher rate of neutropenia with zanubrutinib though. This is consistent with the ASPEN trial in Waldenstrom macroglobulinemia. But also, it didn’t translate to a higher infection rate.

It’s an important study. Again, we don’t have it approved for CLL, but when it becomes available, I also expect ZANU [zanubrutinib] to be a major player. It’s great. As you mentioned, the field is moving toward combinations. Once we have data on single-agent BTK inhibitors, the question is, where are these drugs in terms of having clinical data with different combinations? I would argue that the drug that has a better safety profile is probably going to be a better partner to be added or combined with other regimens. But that’s something we need to wait for, and again we need to be careful making comments in the absence of head-to-head trials, but it’s very promising.

Jonathon Cohen, MD, MS: It’s interesting, you discussed maybe a possible difference, we’ll see with the progression-free survival. The efficacy though did not appear to be different when you look at the ASPEN data in Waldenstrom, where there wasn’t necessarily a significant difference. Although to your point, the toxicity differences did hold, and as you did mention, there was a significant increase in neutropenia for zanubrutinib compared to ibrutinib. Whereas some of the other key toxicities were favorable toward zanubrutinib. This highlights the fact that we’re still learning a lot about these agents and where they fit and also that these are all different diseases. We often think of them as being the same, but what’s better for one disease may not necessarily be better for another disease. With time we’ll hopefully get more data for where individual therapies should be positioned and utilized more frequently.

Mazyar Shadman, MD, MPH: Yes. Thank you very much. It’s a very important point. I just wanted to clarify what you mentioned to our audience. We have 2 head-to-head studies comparing zanubrutinib with ibrutinib. One is in Waldenstrom, the ASPEN trial. That study did not meet the primary end point of an improved efficacy, which was defined as CR or very good partial responses in Waldenstrom in the relapsed group. That primary end point was not met statistically, although the numbers looked better with zanubrutinib, but the study didn’t meet the primary end point. But again, there we saw that the safety profile was better with zanubrutinib except for neutropenia. So that’s the ASPEN trial. For CLL, we have the ALPINE trial in the relapsed setting. There the primary end point was noninferiority and superiority in responses, CR or PR. In the CLL study, that primary end point was met, so there were higher rates of CR or PR in zanubrutinib versus ibrutinib. And again, we saw the same profile of improved safety with zanubrutinib except for neutropenia.

This transcript has been edited for clarity.