What are BTK Inhibitors and how are they used in treating Waldenstrom macroglobulinemia (WM)? Patient Power co-founder Andrew Schorr discusses BTK inhibitors with Dr. Steven Treon, Director from the Bing Center for Waldenstrom Macroglobulinemia, Dana-Farber Cancer Institute as well as the efficacy of Covalent BTK Inhibitors: ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), and tirabrutinib (Velexbru). Dr. Treon reveals when a non-covalent BTK inhibitor may be a treatment option. Dr. Treon recently presented at the 2020 IWMF.

Andrew Schorr:
Hello, and welcome to Patient Power. I'm Andrew Schorr in California. Joining us from Boston and the Dana Farber Cancer Institute is a world-renowned expert in Waldenstrom's, and that's Dr. Steven Treon, who's the Director of the center there.

You and your colleagues now have been very excited about a group of medicines called Bruton tyrosine kinase (BTK) inhibitors. So why is this a big deal for Waldenstrom patients?

How BTK Inhibitors Help Waldenstrom Patients

Dr. Treon:
It's a huge deal because this all started with whole-genome sequencing. And if you really look at the paradigm across many cancers, there's very few where whole genome sequencing identified a mutation. In Waldenstrom's, it's a mutation in MYD88. It occurs in about 95 to 97% of patients. It was discovered in our laboratory with the help of Dr. Peter Bing, and the IWMF who actually financed this. At the time that we did whole-genome sequencing for this disease it was still a very, very nascent art, but it identified this mutation.

Now, you find a mutation, you don't know what that means. Right? Well, thanks to the skill of folks in our laboratory, particularly Dr. Guang Yang, they went about studying what this mutation did. And what they found was that it turned on BTK, Bruton's tyrosine kinase.

It's a very important kinase. It's a protein that actually turns on a lot of different machinery that allows the cell to grow and survive. It also affects the way the tumor cell secretes various cytokines that cause inflammation and allow for the environment around the tumor cell, to allow it to grow and survive. So, it's a big deal knowing that BTK was part of this pathway, but it was all rational. The idea that the discovery of the mutation led to the discovery of BTK, led to the discovery of the BTK inhibitors.

And in 2015, the FDA gave us the first-ever approval for a drug specifically for Waldenstrom's. And I should add, actually, two years earlier than that, the FDA gave us the first-ever breakthrough designation for accelerated drug development because we had this mutation, we have the signaling that it caused, and we had a very rational reason for why BTK inhibitors would be very important.

And as you said, we now have four covalent ones. Covalent ones are the ones that actually bind, and once they bind they don't let go. So ibrutinib (Imbruvica), we have acalabrutinib (Calquence), zanubrutinib (Brukinsa), tirabrutinib (Velexbru). Data with all these different BTK inhibitors shows that they're all very, very active, similar levels of activity. Some differences in side effect profile.

And in addition to that, we also have the non-covalent ones. These are drugs that actually bind, but they can come off depending on what the concentration that we have in the bloodstream. And they don't bind to the same location. That's important because when you develop resistance to ibrutinib, often it involves the same binding point that acalabrutinib and zanubrutinib and tirabrutinib bind. So these other non-covalent ones bind to another part of the BTK molecule and potentially have a very important use in treating patients who became resistant to ibrutinib or one of the other covalent BTK inhibitors.

Is it Possible to Switch Drugs Due to Side Effects?

Andrew Schorr:
If somebody is on, let's say, ibrutinib, and whether, because of side effects or resistance or whatever, could they switch to one of these other drugs without a penalty, if you will?

Dr. Treon:
Well, possibly. I mean, the fact that we're seeing similar levels of activity at this point in time tells me that the opportunity to switch over somebody who's intolerant can be recognized. Now, when we have somebody on a drug like ibrutinib, we often see a side effect being atrial fibrillation. And I think it's important to note that in the vast majority of the patients who get it, we're still able to treat them. We still can continue treatment. We deal with the atrial fibrillation. At around five years follow-up it's about 12% of the patients get atrial fibrillation, but almost everyone continues on ibrutinib with medical management.

Drugs like acalabrutinib, zanubrutinib, which have a little bit shorter follow-up, we are seeing less atrial fibrillation. The head-on trial that was just reported, the ASPEN trial, looking at zanubrutinib and versus ibrutinib head-on showed less atrial fibrillation with zanubrutinib. But there was more neutropenia with zanubrutinib. So there's going to be a yin and a yang with all these drugs.

And the genomics will always be part of the part of the consideration, because if you have MYD88, BTK inhibitors work well. If you don't have it, they don't work as well. If you have the second most common mutation in Waldenstrom's, which is CXCR4, you find it about 40% of patients, that also can slow down the efficacy of these drugs and even see diminished response. So again, having the ability to leverage the knowledge and wisdom of somebody who works in the field is very, very important.

Andrew Schorr:
Thank you so much, Dr. Steven Treon for your leadership, with your lab, with your colleagues there at Dana-Farber and in partnering with others around the world.

Dr. Treon:
Thank you. Thank you for having me.

Andrew Schorr:
I'm Andrew Schorr. On behalf of Patient Power and the IWMF, remember, knowledge can be the best medicine of all.

To view the video interview, please click the link below: