Strategies for Approaching BTK Inhibitor Resistance and Mutations Among Patients With Chronic Lymphocytic Leukemia
At the 2025 Lymphoma, Leukemia & Myeloma (LL&M) Winter Symposium in Miami, Florida, Matthew Davids, MD, MMSc, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses strategies to consider concerning BTK inhibitor resistance and mutations in the treatment of patients with CLL.
Transcript:
I'm Dr Matthew Davids from Dana-Farber Cancer Institute and Harvard Medical School in Boston, and I'm very happy to be here in sunny Miami Beach at the LL&M Winter Symposium. I had the pleasure of speaking at this meeting on BTK inhibitor resistance updates.
I started my talk by focusing on some of the historical data with BTK mutations, particularly in the covalent BTK inhibitors. This goes back to the early days of ibrutinib where the C481S BTK mutation was first identified, but we now have evolving data with ibrutinib to know that that is a very common mutation for patients who do progress. We're also now widely using acalabrutinib and zanubrutinib in clinical practice, and it turns out that this C481 type of mutation is also the most common reason why patients with those drugs develop resistance.
But also with acalabrutinib and zanubrutinib, we've seen a spectrum of different mutations that are less common than we see with ibrutinib. For example, with acalabrutinib, there's a T474 gatekeeper mutation, and with zanubrutinib there's an L528W kinase mutation. Why is that important? Well, it's because we have other BTK inhibitors that are now approved and in development called non-covalent BTK inhibitors. One of them is pirtobrutinib, which received accelerated approval in relapsed CLL. Pirtobrutinib is very active against a wide variety of mutations.
I discussed how effective per ibrutinib is against the C481 BTK mutations, but per ibrutinib can be resistant to certain mutations like L528W, and so this does start to raise questions about the optimal sequence of giving these different BTK inhibitors in practice. We reviewed some of the translational data with ibrutinib showing that the drug can very effectively clear these BTK C481 clones, while at the same time you see outgrowth of the 474 and the L528W clones in the patients on pirtobrutinib.
What do we do for these patients then who are going to progress on pirtobrutinib? In my talk, I also covered some of the exciting new data on BTK degrader drugs. There's 2 of them now, one from Nurix and one from BeiGene. We saw data at the ASH meeting in very heavily pretreated patients with a variety of different genetic mutations, including several different types of BTK mutations. And these drugs led to about a 75% to 80% overall response rate (ORR) in these very heavily pretreated patients, suggesting that this could be a legitimate new option to explore further. It's early days, so we don't know about the durability yet of these BTK degraders, but they certainly do look promising.
In the final part of my talk, I looked at some in vitro data that we looked at looking at different BTK mutations and the activity of all these different BTK inhibitor drugs that we've been discussing. Although it's just lab data, I think it is potentially informative for clinical practice because what you find is a different spectrum of activity of each of these BTK inhibitors against each of the different mutations that we've been discussing.
While right now I wouldn't necessarily recommend routine testing for BTK mutations in all patients with BTK inhibitor therapy in CLL, I do think the field is moving in that direction because you could imagine a scenario in the future where you have a patient progressing on one BTK inhibitor, and then you can do the resistance mutation testing, and that will help to inform the optimal choice of BTK inhibitor in the next line of therapy, based on the pattern of sensitivity that you see.
There is a lot of interesting new data in this space—certainly a lot we need to learn still. Active translational research in this field remains important.
Source:
Davids M. Updates in the Management of BTK Resistance & Mutations. Presented at Lymphoma, Leukemia & Winter Symposium; February 7-9, 2025. Miami, Florida.
