Treatment selection among BTK inhibitors for the first-line treatment of CLL

Bhavesh Shah, RPh, BCOP: Back to our BTK discussion [Bruton tyrosine kinase] inhibitors we have these first generation BTK inhibitors, which believe it or not I still see a lot of ibrutinib [Imbruvica] being prescribed, and now we’re seeing more and more second-generation BTK inhibitors being more important, such as acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. I just want to understand, for patients you are considering a BTK inhibitor for, how do you decide which BTK inhibitor to start with?

Ryan Jacobs, MD: I just want to start by saying that it was really ibrutinib that paved the way for this small molecule inhibitor-based renaissance that we’ve seen in the treatment of CLL [chronic lymphocytic leukemia]. It is an excellent treatment. It has benefited so many patients and should be recognized as such, but now we have other options. In terms of FDA [Food and Drug Administration]-options approved at this point, we have 1 other option which is a second generation BTK inhibitor if you will: acalabrutinib. At first, we only had the kinome trees we like to watch, and we could see that acalabrutinib had much less off-target kinase inhibition and just seemed like a cleaner drug. Then, clinically, we were seeing maybe less toxicities or lower quality toxicities in general in our clinics. We had these between-trial comparisons that we could make between the 2 and the matched, adjusted, and integrated comparisons. Now, fortunately, we were able, in manuscript form, to have recently published the ELEVATE-RR [clinical trial] data, which compared ibrutinib with acalabrutinib in a high-risk relapsed CLL patient population. I feel like the conclusions we drew from this study supported what we thought that toxicities were lower with acalabrutinib and dropout rates due to toxicities were lower. Specifically, atrial fibrillation, which was one of the secondary endpoints, was lower. Now, I think it’s reasonable to refer to acalabrutinib as a better tolerated BTK inhibitor. When I talk about BTK inhibitors I always say that it is important to understand how these drugs are similar and how they are different when making treatment decisions as they treat CLL and their covalent Bruton inhibitors tyrosine kinase. . They do it by bonding at the same time C481S binding half. That’s why in this ELEVATE-RR study, which was a non-inferiority trial and was the primary endpoint, it showed non-inferiority between the 2. In terms of efficacy, you wouldn’t expect not necessarily that 1 is greater than the other. Certainly, if you had a patient who had progressed on ibrutinib, I wouldn’t consider acalabrutinib as a treatment option for them because they would also have to be resistant to acalabrutinib and most likely have a mutation at that time. C481S binding sign. Now we have head-to-head data to say definitively that there is a lower incidence of dropouts due to adverse events with acalabrutinib, specifically lower rates of cardiac toxicity. I think it’s reasonable at this point, and that’s what I do in my clinic, that if I’ve decided the patient is going to be treated with a BTK inhibitor, then I start the conversation with acalabrutinib at this stage. However, there are still situations where you might need an option other than acalabrutinib. The most obvious is the contraindication to taking a proton pump inhibitor with acalabrutinib. Some patients really need their proton pump inhibitor. They cannot be downgraded to H2 [histamine 2]-receptor antagonist, ibrutinib is therefore an excellent option for these patients. Sometimes you’ll come across situations, it’s happened to me several times, where there’s a contraindication like that to acalabrutinib, and maybe they’ve been on ibrutinib before and had a toxicity problem, and I’m looking for another option. This is where it’s nice to have, in an off-label format, the ability to use zanabrutinib, for which some data has been reported at this stage on its efficacy in CLL and its tolerability. It’s not technically cleared by the FDA yet, but it’s now on the NCCN [National Comprehensive Cancer Network] guidelines, so I was able to get it approved off-label in the specific circumstances where I needed it.

Bhavesh Shah, RPh, BCOP: I couldn’t agree with you more. I really think I’m emphasizing the off-target impact of EGFR [epidermal growth factor receptor] and JAK 3 [Janus kinase 3] and R2, which really bring to light some of these toxicities that you were talking about, like atrial fibrillation, bleeding, and hypertension. It’s like we’re making these agents better and better where we have more choices for patients. It’s amazing what some companies are doing, like the makers of acalabrutinib reformulating acalabrutinib to actually be delivered with the PPI [proton pump inhibitor], because currently you can’t. They developed the formulation, which is a formulation of maleate tablets that you can actually administer through a nasogastric tube or with a PPI, so it will be really interesting to get rid of the interaction that providers are always concerned about. I think it’s amazing for a manufacturer to go to such lengths to reformulate, because they know the impact of these drugs on patients is so great. It sounds like you’re definitely headed for acalabrutinib, and if there are concerns about drug interactions, then zanabrutinib is kind of your other choice.

Transcript edited for clarity

Martin E. Berry