Head-to-Head Studies on BTK Inhibitors in CLL


CLL expert Lori A. Leslie, MD, gives a comprehensive overview of the ALPINE and ELEVATE-RR head-to-head studies of BTK inhibitors in CLL.


Lori A. Leslie, MD: We now have 3 covalent BTK [Bruton tyrosine kinase] inhibitors approved in CLL [chronic lymphocytic leukemia]. We talked a bit about the frontline setting, and the relapsed/refractory setting is different. In the front line, we talked about BTK inhibitor vs chemotherapy mostly, and in relapsed/refractory, we have head-to-head data looking at that first-generation BTK ibrutinib vs the next-generation BTK inhibitors, acalabrutinib or zanubrutinib.

I want to mention 2 studies, the first is ELEVATE-RR. That is a randomized study, so flip a coin, patients either get ibrutinib, which is the first generation, or acalabrutinib, which is the second generation. This specifically was focusing on slightly higher-risk patients who had certain molecular abnormalities, particularly 11q deletion or 17p deletion. This was a noninferiority study, which means it was done to prove that acalabrutinib, the newer BTK inhibitor, had the same efficacy as ibrutinib on an end point called progression-free survival [PFS]. That was found to be noninferior, the PFS was the same, but some secondary end points that emerged were the differences in safety. In particular, the cardiovascular toxicity profile of acalabrutinib was favorable compared with that of ibrutinib. This was one of the studies that helped us look at the medications head-to-head, not only from an activity perspective, but importantly, they have a similar mechanism of action, is one tolerated better than the other? The consensus from some of those secondary end points, particularly from a cardiovascular end point like atrial fibrillation, is that acalabrutinib is favored over ibrutinib.

There was a similar finding that came from the ALPINE study, which is also a randomized study in relapsed/refractory CLL, and is looking at patients who either could get ibrutinib or zanubrutinib, which is another next-generation BTK inhibitor. The end point of this study was a little different. This is a superiority study, meaning it was designed to potentially show that zanubrutinib is better or superior to ibrutinib. The primary end point was overall response, and that’s an important end point. That favored zanubrutinib over ibrutinib, showing that more patients had at least a partial remission or better. Something that was presented recently at our big blood cancer meeting, ASH [American Society of Hematology], at the end of last year surprised us, and that showed that zanubrutinib was superior to ibrutinib in terms of progression-free survival. People stayed in remission responding to therapy at the 2-year time point more commonly with zanubrutinib compared with ibrutinib.

This potential efficacy difference—it was a secondary end point—is really encouraging that not only are these newer agents better tolerated—that also panned out that zanubrutinib had a favorable cardiac toxicity profile compared to ibrutinib—but potentially we’re seeing an efficacy signal. Another thing that the development of zanubrutinib has done very nicely is they’ve teased out this higher-risk patient population that is 17p abnormal. This benefit over ibrutinib was not only in the whole population in terms of progression-free survival, but also was seen significantly in those with TP53 or 17p abnormal CLL. [These are] exciting results to show that not only are these new agents potentially better tolerated, but further follow-up will let us know if this difference in progression-free survival is durable and something we see with more time.

Transcript edited for clarity.

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