BTK Therapy for the Frontline Treatment of CLL - Episode 4

Key Takeaways from the ELEVATE-TN Trial in CLL

John M. Pagel, MD, PhD:One of the things that’s very exciting is in regard to the newer BTK [Bruton tyrosine kinase] inhibitors that are emerging—acalabrutinib, and we haven’t talked about zanubrutinib, but that’s on the immediate horizon. These newer-generation BTK inhibitors, and I should also say there are several in development, are really suggesting to us that we have more tolerable therapies that will translate to better outcomes for patients if they can stay on the treatment as long as possible. There is a difference between these agents. Right now, we have 2 approved agents that are BTK inhibitors. They’re what we call irreversible, or covalent BTK inhibitors. They both bind to the Bruton tyrosine kinase binding pocket in the exact same way with the exact same amino acid context. We’re talking about ibrutinib and acalabrutinib.

What’s different between these tyrosine kinase inhibitors is that they have different kinases that they hit as off-target binding sites. Certainly, we want them to be very selective for BTK, and ibrutinib and acalabrutinib are both highly selective for BTK. However, acalabrutinib is actually, maybe, what we would call a cleaner kinase. It hits fewer off-target kinases than ibrutinib. That may be an advantage. You could argue in some cases that it might be a disadvantage. But in general, the idea is that if you can hit fewer off-target kinases with your tyrosine kinase inhibitor, like acalabrutinib, maybe you’ll have fewer adverse effects. The early data, albeit not head-to-head comparative data, suggest that acalabrutinib may be better tolerated than ibrutinib.

We know that if you look at a kinome profile or a map of the kinases that each of these drugs interact with, there are way fewer kinases that are interacting with acalabrutinib than there are with ibrutinib.

In fact, we are able to assess the tolerability of these agents through the trials that we’ve done. The ELEVATE-TN trial—the frontline trial of acalabrutinib either with or without obinutuzumab—was again compared with chlorambucil and obinutuzumab. The efficacy was outstanding—about a 90% reduction in the risk of relapse, progression, or death—if you got acalabrutinib with obinutuzumab versus the chlorambucil-containing regimen. We saw significant outstanding efficacy, which is very similar to what we see with ibrutinib as well.

What was very important from the ELEVATE-TN trial, I think, was the outstanding tolerability of the therapy. Less than 10% of patients had to discontinue treatment at a median follow-up of about 2 years or 2½ years. This tells you, again, a lot about the tolerability of the therapy. If you look at the adverse events, they’re almost always grade 1 or grade 2. Most of them are usually self-limited. There are some myalgias, arthralgias, perhaps a rash, but their rates are very low. They may be very low because you’re not hitting all those off-target kinases.

As an example, we know that acalabrutinib does not targetEGFR. So we see relatively low rates of rash or diarrhea because we’re not hittingEGFR. We also, of course, are always concerned about more serious related adverse events due to the BTK inhibitor. In the ELEVATE-TN trial, the rate of atrial fibrillation was very low—about 2%. We certainly need to follow patients for a longer period of time, but this is a very encouraging low rate of atrial fibrillation, relatively speaking, and bleeding as well. Major bleeding was on the order of about 2% as well, and that was very similar, whether you were on an anticoagulant or an antiplatelet agent, or you were not. Major bleeding was very low with acalabrutinib. Overall bleeding, such as bruising and contusions, or other signs, such as purpura, were on the order of about 8% or so.

We do know that the ELEVATE-TN trial shows us outstanding efficacy with acalabrutinib and, potentially, a significantly improved tolerability profile. Now, I have to be clear: We don’t have head-to-head comparative data between ibrutinib and acalabrutinib yet. That trial has actually been done. We’re waiting for the data. We should have that in about another year or so—maybe sometime in the middle of 2021. We’ll have an answer as to whether 1 of these 2 agents is better than the other. That will be very important to document.

Transcript edited for clarity.