iwNHL 2024 | Targeting BTK to treat CLL and NHL: insights from BTKis and novel BTK degraders

Tanya Siddiqi:

We just had a great session at iwNHL on novel therapies in lymphoma as well as CLL. You guys talked about BTK inhibitors and BTK degraders. I went over some venetoclax data. Krish, why don’t you tell us about BTK inhibitors and lymphomas?

Krish Patel:

Yeah. It was a really great session. We covered the spectrum of BTK inhibitors that have been developed to this point, so the entire class of covalent inhibitors. Alexey, really, I think, nicely summarized for us that even the earliest drug in the class ibrutinib may still have a role when we think about, really, the fine details. When it comes down to the specificity of drugs, in some cases, immunomodulatory effects of a less selective inhibitor might be important.

Tanya Siddiqi:

Namely ibrutinib.

Krish Patel:

Namely ibrutinib. The longevity of the data we have there. The reality is we are, I think, in some ways, spoiled for choices because we can really parse the details of toxicity between first-generation and second-generation and now coming into third-generation to really try to find the right fit for each patient. But the reality is the entire experience of giving BTK inhibitors in Waldenstrom’s, marginal zone, mantle cell lymphoma, CLL has been a really positive thing for patient outcomes.

Tanya Siddiqi:

And now pirtobrutinib is being tested in a lot of these-

Krish Patel:

That’s right.

Tayna Siddiqi:

…diseases as well.

Krish Patel:

Yeah. One question that I think you raised which is really important is to understand what’s the optimal sequence going to be. We know pirtobrutinib can be an effective therapy in patients who have already had covalent BTK inhibitors across the spectrum of B-cell malignancies. But the right question really is when should we be using it, and is it going to ultimately supplant covalent BTK inhibitors can really only be answered by prospective studies.

Tanya Siddiqi:

Then for people who progress after BTK inhibitors, including maybe even the non-covalent BTK inhibitor, pirtobrutinib, I think the BTK degraders are looking really useful in CLL at least, and maybe other diseases, too.

Alexey Danilov:

Yes, absolutely. This is a very exciting novel therapeutic, which is a proteolysis targeting chimera. There are several BTK degrader molecules in clinical development currently. There is data with several of them already. What’s important is that BTK degraders are active against Bruton’s tyrosine kinase, which carries mutations which confer resistance to BTK inhibitors. It is, indeed, the next step, although in the future, potentially, we may also investigate these drugs in earlier lines of therapy. But we’re not there yet.

Currently, there is good data which exists with several compounds produced by Nurix and BeiGene, and they look very good in terms of safety and efficacy. Indeed, Phase I clinical trials in CLL have demonstrated that patients who have progressed on pirtobrutinib actually responds to BTK degraders. The response rates are high, 70%, and ongoing, and responses are durable. I personally have patients who have taken BTK degrader for over two years now who have multiple refractory CLL. There are also good responses in non-Hodgkin lymphoma subtypes including mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma. There is certainly very good emerging efficacy data with these drugs. In terms of safety, so far, very limited safety signals: BTK inhibitor-like adverse events, some bruising, contusion, some mild cytopenias, but very few grade three events with all the drugs presented today.

Tanya Siddiqi:

Can I ask specifically about cardiac toxicity? Because with the BTK inhibitors, we worry about atrial fibrillation specifically. Is there any with BTK degraders?

Alexey Danilov:

Yeah. That’s a very good question. Of course, the follow-up on this early-Phase trial is still pretty short. We are talking maybe 12-month follow-up. With NX-5948, there is so far no signal for atrial fibrillation. Same thing with the BeiGene compound: so far, no cardiac toxicities. But as you know, some of these toxicities… They occur later, such as hypertension. I think we’ll just simply need longer follow-up.

Tanya Siddiqi:

Even with pirtobrutinib, I think it’s less cardiac toxicity than with the covalent BTK inhibitors, we think.

Krish Patel:

That’s right.

Tanya Siddiqi:

Although not zero.

Krish Patel:

That’s right. I think Alexey’s point is a really good one. It wasn’t really until we had long-term follow-up of ibrutinib and then longer follow-up of acalabrutinib and zanubrutinib that we were really able to parse some of these differences. I think the same will be true for pirtobrutinib. We’re starting to get there. The study has now shared several different readouts of aggregated safety data. I do think, overall, the profile looks really, really good and certainly what we have become accustomed to with second-generation covalent BTK inhibitors. But you’re right. I think late toxicities that emerge like hypertension or very rare events really need a lot of long-term follow-up.

Tanya Siddiqi:

Yes, we learned a lot from this novel therapeutics section in iwNHL in Nice today. We heard about BTK inhibitors and BTK degraders, which are some of the best drugs in some of the lymphomas that we treat.