Resistance to BTK Targeted Therapy in CLL

Alan Skarbnik, MD: In terms of resistance, we know that ibrutinib resistance is mainly driven by BTK [Bruton tyrosine kinase] mutations. PLC-gamma-2 is downstream for that as well, although not as common. Is this the same with acalabrutinib?

Jennifer R. Brown, MD, PhD: The Ohio State Group reported at ASH last year that they did detect the same type of resistance mutations in patients on acalabrutinib as on ibrutinib. These were detected at a median of about 33 months on therapy, mostly in the relapsed setting. There was about a 1-year lag between when they detected them to when the patients progressed.

They did suggest the possibility that they were detecting these mutations a little bit earlier in patients who had switched from ibrutinib to acalabrutinib. We don’t really have long-term data about whether it holds true in the setting of problems and then switching to acalabrutinib might contribute to resistance. The patient numbers are very small, so it’s hard to tell. But part of the reason I lean toward using acalabrutinib first is because I think that it’s probably better for the patient not to get a serious toxicity in the first place. In my experience, toxicity has been much less with acalabrutinib. This is a better approach than letting them get it and then hope it goes away when you switch to a related drug in the class.

Alan Skarbnik, MD: Yeah, I completely agree with that. That’s why I’ve been favoring acalabrutinib as well.

Jennifer R. Brown, MD, PhD: We do have next-generation noncovalent BTK inhibitors that are targeting this C481 mutation. In particular, 2 of them had very nice data in terms of responses. The ArQule, Inc drug and LOXO-305 are looking quite promising in patients who have these mutations. The noncovalent drugs are able to inhibit the mutation as well as wild-type disease.

Alan Skarbnik, MD: Yeah. And then from the phase 1 data, at least from LOXO-305, it looked like the toxicity profile was very, very encouraging. Do you think that’s because of the reversibility of the BTK inhibition?

Jennifer R. Brown, MD, PhD: That’s an interesting question. I think that maintaining intense pressure on BTK is probably important for efficacy. I’m not sure that the reversibility is helping, except if there are some minor off-target effects where the drug is much less potent. Then, maybe the reversibility is helping. But LOXO-305 is the most specific BTK inhibitor of any of them out there, covalent or non-covalent. It’s really quite specific. So, I think that is probably substantially contributing to what appears to be the very excellent toxicity profile.

Transcript edited for clarity.