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Latest News on BTK Inhibitors for CLL

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Published on August 20, 2020

What BTK Inhibitors are Approved for CLL?

How do BTK inhibitors work for CLL? How do experts decide when to put a patient on one? If you have been on one inhibitor, can you try a different one? Host Andrew Schorr gets the answers to these questions from CLL expert Dr. Richard Furman from Weill Cornell Medicine. Dr. Furman explains why he believes that BTK inhibitors long term have better outcomes than the other oral agents. Watch the full interview.

This is Part 1 of a 4-part series on CLL. Watch all segments in the series below:

This program is sponsored by AbbVie, Inc., Genentech, Inc. and Adaptive Biotechnologies. These organizations have no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | Latest News on BTK Inhibitors for CLL

Andrew Schorr:

Greetings. Welcome to this CLL Ask the Expert program. I'm Andrew Schorr, joining us in California and also, we're going to have a leading CLL expert join us live from New York, and here he is, Dr. Richard Furman. Dr. Furman is the Director of the CLL Research Center at Weill Cornell Medicine in New York City, and New York-Presbyterian Hospital. Dr. Furman, welcome to our program.

Dr. Furman:

Thank you. It's actually great to be here, and I'm looking forward to speaking with everyone.

How are BTK Inhibitors Used to Treat CLL?

Andrew Schorr:

Okay. We've got you, I would say, in the hot seat today. I want to thank our sponsors, AbbVie, Genentech, and Adaptive Biotechnologies for supporting this program. Of course, we retain editorial control.

Okay. Let's start with the oral therapies. So, we've got BTK inhibitors, and we have a couple that are approved, maybe others that are coming. We have another kind of oral therapy, venetoclax (Venclexta) First of all, how do you know... are they all the same? They're all pills, but they're not the same, are they?

Dr. Furman:

So I think the most important thing to think about whenever you talk about a therapy, and it doesn't matter if it's oral or intravenous, is really what's the mechanism of action, what's its efficacy, and what are its side effects. Let me just clarify some very important issues that I find that most patients have trouble understanding. When we look at BTK inhibitors, and BTK stands for Bruton's tyrosine kinase. This is an important enzyme, it's very important to B-cells, but it is present in a lot of other cells as well. And what we find is that in kids who have no BTK, they actually have no B-cells and so it made great sense to be a target for B-cell lymphomas. Inhibiting BTK does have a lot of issues beyond just the B-cells, and that's why we see a lot of the adverse effects.

We currently have three approved BTK inhibitors, ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). I like to consider ibrutinib to be the first generation, and acalabrutinib and zanubrutinib to be the second generation and I'll explain why in a moment. But what's similar among the three of these is they all bind to the exact same amino acid residue in the pocket, the active pocket of BTK. And so that they all have to covalently bind to a cysteine there to shut down the BTK enzyme. And so, they all work exactly the same way and so, I do expect them to all work under the same circumstances and with the same efficacy by and large. The differences that we see between these really are due to their off target effects. So, ibrutinib, which inhibits the group of enzymes that are called the Tec kinases actually has some side effects related to inhibition of those other kinases.

So inhibiting Tec kinase, and BTK leads to platelet dysfunction and bruising and inhibiting the EGFR or the epidermal growth factor receptor leads to rashes and diarrhea. Now, as it turns out, acalabrutinib and zanubrutinib are actually more specific to BTK than ibrutinib.

Andrew Schorr:

Dr. Furman, some people though have had fibrillation issues with ibrutinib, right? So heart issues, if you will, and they have to be switched. That's another one. Right?

Dr. Furman:

So one of the things about the... we don't understand the mechanism for the atrial fibrillation that we see with ibrutinib. We don't see it with acalabrutinib and zanubrutinib, and that's an important distinction. While we really don't know what causes it, we do know that it's real and it is associated with ibrutinib.

Andrew Schorr:

One of the questions we got, somebody said, well, if you've been on one of these novel agents first and have to switch for some reason, are you precluded from going on another? I think the answer is no, but you tell us.

Dr. Furman:

So it's really important to keep in mind that since all three of these BTK inhibitors work exactly the same way, actually progressing or having resistance to one of them will translate into resistance into the others. If you progress on ibrutinib, acalabrutinib will not be of benefit. There is what I call the third generation, which are the reversible BTK inhibitors, which don't require that cysteine, that amino acid and the act of pocket of BTK. And so they therefore actually could work in some of the mechanisms of resistance to the covalent BTK inhibitors. And so those may work. Now, as it turns out, with regard to other oral agents, we also have the BCL-2 inhibitor venetoclax, the PI3 kinase inhibitors idelalisib (Zydelig) and duvelisib (Copiktra) being resistant to one or having one first and then progressing, doesn't preclude the use of any others. These are not cross resistance and unlike chemotherapy progressing on one doesn't necessarily predict for being more resistant to the others.

Andrew Schorr:

Okay. Somebody wrote in and just asked about pulmonary issues as a side effect on ibrutinib and wondered if you've seen pulmonary side effects.

Dr. Furman:

I've not seen pulmonary side effects related to ibrutinib by and large.

Andrew Schorr:

Okay. And so part of the choice, and we have a lot of people as you know, CLL who are in watch and wait. And so then you're trying to decide, well, do you start in this direction with a BTK inhibitor? Which one? Or do you go to a BCL-2 inhibitor or other inhibitors? How do you make that decision? Is some of it, whether somebody has atrial fibrillation issues going in, or how do you decide which way to go?

Dr. Furman:

We all have our biases. And I actually do believe that BTK inhibitors long term have better outcomes than the other oral agents. And the truth is, we do have seven year data for ibrutinib, which I do believe is equivalent to the other BTK inhibitors. I speak to them all as a class, but I do think BTK inhibitors by and large are more efficacious. And so they're often my first choice. Some patients though prefer what might be offered by venetoclax in the terms of the fact that it's usually a fixed duration. It's a once a day pill, whereas the acalabrutinib and zanubrutinib tend to be twice a day, there are a lot of subtleties and also other comorbidities that may direct the physician and patient in one direction versus the other.

Just one thing I do want to mention and report on is currently venetoclax is approved for use in combination with either obinutuzumab (Gazyva) or rituximab (Rituxan) for durations of one or two years. It's important for patients to remember that we really don't know what is the ideal duration of treatment.

The way I phrase it is we don't know if stopping treatment after one year is not necessarily depriving the patient of some of the benefits. I've always been very cautious and I always warn patients that just because that's the way the regimen was approved, doesn't mean that's the best way to use the drug.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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