Resistance to Ibrutinib in CLL



William G. Wierda, MD, PhD: Let’s talk a little bit about ibrutinib resistance. Maybe, Anthony, you can comment on mechanisms of ibrutinib resistance and testing that we might do and how you use those tests, if you do or don’t in the management of your patients.

Anthony R. Mato, MD: I think ibrutinib resistance is an area where there’s a little bit more data than venetoclax resistance, but it’s still relatively early. I think early on the thought was that all CLL [chronic lymphocytic leukemia] progressions were secondary to BTK [Bruton tyrosine kinase] mutations that would ultimately render ibrutinib unable to bind, or downstream PLC-gamma-2 mutations that would be activating and making BTK irrelevant in the signaling pathway. Over time what we’re learning is that that’s probably a major driver of resistance, but there are still a significant minority of patients who progress who they can’t find either mutation present.

I think ibrutinib resistance mutation testing is still largely a research question only, and I would argue most major academic centers probably don’t have that in-house at this time. We do have that testing available, and I do sporadically test, but I have to say that I don’t really have a worked-out algorithm for how and when I should be doing it and when I find it outside of clinical progression, what I should be doing with those results. And when I do test for it in the setting of progression, it’s almost a so what because I don’t have a drug that I could use that’s FDA approved at the moment [for which] those testing results would really matter. Largely, those patients are treated with venetoclax in 2018 whether they have the mutation or not.

I think an area that’s interesting, or there are several noncovalently binding BTK inhibitors that are in varying stages of development, some not in patients yet, some in 20 patients, and some in between where they may be able to overcome the BTK side of the resistance for patients who have ibrutinib resistance. I think it remains to be seen right now. The doses are too low, but that’s a promising area. For downstream activating mutations, I think right now there is no viable strategy from a BCRI [B-cell receptor inhibitor] signaling perspective, and all of those patients should receive venetoclax.

William G. Wierda, MD, PhD: Speaking of the reversible inhibitors, Susan, you can touch on a little bit in terms of what we’re looking at now with reversible inhibitors and what we should be hearing about perhaps next year [2019] at ASH [the American Society of Hematology Annual Meeting & Exposition] about that category of new drugs.

Susan M. O’Brien, MD: Anthony mentioned there are a couple of companies that have these. The 2 that have posters this year [2018] were all phase I, so they’re very early. The rationale is that if you have binding outside the binding site for ibrutinib, that if patients develop the BTK mutations, because these noncovalent inhibitors bind in a different site, that they would still have activity. And, certainly, preclinically, they appear to be active against both the wild-type and the mutated strains in the lab. And that’s the rationale behind going to them, which would be nice because if they were active and relatively safe, you could change an ibrutinib-resistant patient to one of those agents and still have venetoclax in your back pocket. So it would be nice to have this whole other, we won’t call it a class because it is a BTK inhibitor, but a different class of drugs that would work.

Clinical data is super early. There’s some suggestions that there is some downregulation of phospho-BTK. There is suggestion that in both the trials that they’re beginning to have some biologic activity. I don’t think there were, I don’t remember if there are actually any true responses, but there were some people whose lymph node shrank a little bit. There’s no MTD [maximum tolerated dose] that’s been reached so far. So all I would say is [it’s] extremely early, very promising potentially based on the laboratory data, and I imagine the difference between this year and next year is that since these trials just started, hopefully there will be significantly more data on them at ASH next year.

Alexey V. Danilov, MD, PhD: Susan, considering the allele frequency discussion that we had, do you think it might be a better strategy to continue patients on ibrutinib and add the noncovalent inhibitor?

Susan M. O’Brien, MD: I think that’s an interesting idea, yes. I think that would be a tricky way to get the drug approved, so I suspect that that’s not going to be the registration trial. But it raises a very interesting point, particularly that we know that when we have the BTK mutations, what that does, right, is make ibrutinib noncovalently bind. But there’s still activity. It’s just a competitive binding, and that’s why we all know that when we have patients who start to develop clinical resistance on ibrutinib, we never stop the ibrutinib until we have a plan in place. And the reason they progress so slowly on ibrutinib is that you’re still getting partial control of the disease because you still are having binding. It’s just not irreversible binding.

I actually have a patient who wanted to shop around and look for interesting trials, and he was on ibrutinib becoming more and more resistant for like 9 months. But his disease was still controlled and then he found a trial he wanted to go on. You can really maintain them. I’m not suggesting we leave our patients on ibrutinib till they blow up, but you really have a window there where you can look around, decide what you want to do before you stop it. I think probably what most of us do when we’re using venetoclax is not stop it until we get to the 400 mg dose. And I’ve actually seen patients referred to me early on in the days of venetoclax where the ibrutinib was held, and they could not get through the ramp-up because they had such explosive disease. So I’m betting when all of us, when we have an ibrutinib-resistant patient that we’re going to switch to venetoclax, we continue the ibrutinib till we know we’ve gotten to the effective dose of the venetoclax.

William G. Wierda, MD, PhD: Is that the consensus?

Matthew S. Davids, MD, MMSc: Yes, we do that as well. I think we do need to be mindful that there is a recently identified drug-drug interaction between ibrutinib and venetoclax. And so when we’re giving ibrutinib and we’re continuing it, the venetoclax exposure is probably higher, maybe upwards of 2-fold higher than what we previously thought. So we do that, but we do it cautiously and we monitor very closely for TLS [tumor lysis syndrome].

Transcript Edited for Clarity

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