A 72-Year-Old Man with R/R Chronic Lymphocytic Leukemia - Episode 6

Emerging Treatment Options for Patients with R/R CLL

A detailed description of emerging treatment options for patients with relapsed/refractory CLL.

Catherine Coombs, MD, MS: There are a number of emerging strategies that are exciting with respect to therapies for patients with CLL [chronic lymphocytic leukemia] in the relapsed/refractory setting. The first one I’ll go through is zanubrutinib. Somewhat similar to acalabrutinib, zanubrutinib is a newer-generation covalent BTK [Bruton tyrosine kinase] inhibitor that is more selective for BTK, its target. The idea is that if it’s more selective, it’ll have less off-target toxicity and should be a better tolerated drug. ALPINE was a randomized trial comparing zanubrutinib to ibrutinib in patients with relapsed-refractory CLL. This was presented at EHA [European Hematology Association annual meeting] in 2021. What it showed is that zanubrutinib had remarkably low rates of one of the most bothersome toxicities, atrial fibrillation. Of the patients who were treated with zanubrutinib, only 2.5% had any grade atrial fibrillation or flutter compared to ibrutinib’s 10%. They have similar rates of hypertension, though. That’s one thing that isn’t quite as good as acalabrutinib, but certainly a very attractive low rate of atrial fibrillation. The caution is that the follow-up on this is very short, I think it was just over a year. I think we need to see a little more time pass before we can say that this agent is the best tolerated. I don’t think we’ll ever know that because we don’t have a head-to-head trial on zanubrutinib versus a acalabrutinib, but this is very attractive. The other exciting thing from this study is that on the early look, it appears it may have a bit of an edge with respect to PFS [progression-free survival], but we need more follow-up to make sure that signal holds with longer time.

The other drug that’s gotten a lot of press is pirtobrutinib. This is a BTK inhibitor, however, the big difference is that this is noncovalent. Acalabrutinib, ibrutinib, zanubrutinib, these are all covalent BTK inhibitors, and for them to inhibit BTK, they need to form a covalent bond at C481. What we know from studies from Jennifer Woyach, [MD,] out of [The Ohio State University], among others, is that the most common mechanism of resistance to covalent BTK inhibitors is a mutation at that binding site to where the drugs can no longer bind and inhibit the protein. Pirtobrutinib by binding in a noncovalent reversible fashion is agnostic to whether that mutation is present or absent because it inhibits that protein at a different binding site. This is a very attractive drug. It was studied in the phase 1/2 BRUIN trial. This has subsequently been published in The Lancet in 2021. What this shows is that this drug has high overall response rates in a pretty heavily pretreated CLL population, with an overall response rate of 63%. Though some looks at the data show that this overall response rate may increase with increasing exposure to the drug. The other area where this drug really shines is it is very well tolerated. Only about 5 out of the 300 some patients on that Lancet publication discontinued due to toxicities. It was a phase 1 trial, but they did not reach a maximum tolerated dose given that no DLTs [dose-limiting toxicities] occurred. That’s the other area where the drug shows real benefit for patients, in that it may not have the same degree of tolerability issues that some of the covalent BTK inhibitors have.

The last exciting new drug is umbralisib. This drug is a PI3K inhibitor, and there was a large phase 3 trial, UNITY-CLL, that compared umbralisib with ublituximab, which is a novel anti-CD20 drug, somewhat similar to obinutuzumab in that it’s glycoengineered. This combination, they call it U2 [umbralisib and ublituximab], was compared to chlorambucil with obinutuzumab, and it showed superior PFS for the [umbralisib and ublituximab]-treated patients compared to chlorambucil and obinutuzumab. It was an interesting study because it included both frontline and relapsed/refractory patients. It’s not yet FDA approved. The last that I heard, this study was up for review, and it’s been put on hold because there may be increased deaths in the [umbralisib and ublituximab] arm. It’s attractive from a PFS standpoint, but I think the OS [overall survival] data need to be looked at a bit more closely before knowing whether this is something that should be made available to patients. The one very nice thing about umbralisib when looking at the other PI3K inhibitors that are FDA approved, duvelisib and idelalisib, is that the tolerance seems quite a bit better with umbralisib compared to the older agents. But tolerance remains an issue, and infections certainly are a concern with these drugs as a class.

I think all of these studies do inform our next steps in CLL as a field. My personal view is that the reversible BTK inhibitors are very attractive and exciting methods of treating patients with CLL in the relapsed setting, but they may also be able to move into the front line given their potentially superior adverse effect profile. To my knowledge, there are a number of phase 3 trials studying pirtobrutinib, both in the front line in planning, and in the relapsed/refractory setting against comparators of clinical interest. There are also other reversible BTK inhibitors under development. One is ARQ 531, which is now MK-1026. Then there’s also vecabrutinib, though that drug is no longer under clinical development, due to suboptimal efficacy in its phase 1b trial.

Transcript edited for clarity.