iwNHL 2023 | Novel therapies in NHL: BTK inhibitors & degraders

Tanya Siddiqi: Hi, I’m Tanya Siddiqi. I’m a hematologist from City of Hope Medical Center in Southern California, and I have with me Dr Nirav Shah, who is a hematologist from the Medical College of Wisconsin. We just had a great session on novel therapies, talking about BTK primarily. The session is called BTK inhibitors, but we also talk about BTK degraders- which is why I just call it BTK. We started with talking about zanubrutinib, acalabrutinib, and then you talked about pirtobrutinib. So that’s the exciting new non-covalent-binding BTK inhibitor. If you want to tell us a little bit about the data you presented?

Nirav Shah: Of course! Thanks Tanya, and it was a great discussion today. So I think pirtobrutinib is a little bit different to the drugs we’ve talked about so far. It’s a non-covalent inhibitor, sort of first-in-class drug, the first in that generation to be approved in relapsed/refractory mantle cell. What’s important about it is the different mechanism of action, and so it can actually inhibit BTK even in those patients who have progressed on covalent BTK inhibitors or those who have a mutation at the C481 site, making the covalent inhibitors no longer effective. We shared some data today looking at its efficacy across B-cell malignancies- which I thought was relatively impressive, with high rates of overall response in BTK-exposed CLL, BTK-exposed mantle cell, and even difficult-to-treat diseases like Richter’s. The safety profile of the drug looks very compelling, especially when we think about traditional BTK toxicities such as AFib, hypertension, bleeding; which was very low in the BRUIN trial, which enrolled over 700 patients. So I think this is definitely a drug that has a place in B-cell malignancies, but as I showed at the end, it’s not the end all be all. Resistance mutations can occur to non-covalent BTK inhibitors, and luckily, you talked about what we can do for that group of patients.

Tanya Siddiqi: Right. So we talked a little bit about early data that we’ve seen so far from the Nurix BTK degrader trial, the 2127 program. That’s a product that basically uses the ubiquitin-proteasome pathway to degrade the entire BTK complex, but also that particular product has an effect on cereblon as well and leads to degradation of that protein as well, thereby leading to a two-target effect of this fairly well tolerated treatment modality. It’s oral therapy. The trial enrolled patients with various B-cell lymphomas, including CLL, and the responses were a modest 33% overall response rate, but all the patients had had prior BTK inhibitor therapy, including one or two with pirtobrutinib failures as you mentioned. A majority of the patients were also double-class exposed to BTK inhibitors as well as venetoclax, so BCL2 inhibitors. So it’s this growing population in CLL, especially where we don’t have a lot of good options for people who are failing our two best targeted therapy treatment modalities. The company has come up with a new product, the 5948 product, which is also an oral pill- and that basically just degrades the BTK. It doesn’t have the cereblon side effect because on the 2127 program, they saw a little bit too much neutropenia as a side effect, and we think maybe it was the cereblon effects that were leading to the neutropenia. So on this new phase of the study, it’ll be nice to see if that side effect goes away. The study is now enrolling, it’s taking all B-cell lymphomas, including primary CNS lymphoma, because they have penetration into the CNS, and we don’t have data yet. So that’ll be something we’ll discuss in the future. There aren’t a lot of other BTK degrader programs out there, but the Nurix ones are the best, most developed- both trials are enrolling still. We’ll see if the treatments are useful in a number of other B-cell diseases, not just CLL. So exciting time in CLL and lymphomas, with all sorts of new targets coming along.

Nirav Shah: Yeah, I think it’s great that we didn’t stop at covalent BTK inhibitors and say that once you’ve exhausted those, that that pathway is no longer accessible. So I think that between the non-covalent, the degraders, and whatever comes next, we can sort of re-establish BTK inhibition and prolong patient’s duration of response with- I think- well-tolerated oral agents. So that’s really an exciting development, and it was a fun conversation to have today about the future of this field, which is, which drug do you give first?

Tanya Siddiqi: Yeah, and I think some of the other discussions that occurred with the acalabrutinib and zanubrutinib showed the reason why we need so many different agents in this pathway, that there are potentially some side effects- more so than ibrutinib- hypertension, bleeding, neutropenia, et cetera. Then resistance mutation, as you talked about. So there is a need to develop all the fields further, and I think this was a great session to summarize all that.

Nirav Shah: Yeah, agreed. Thanks.