Second Generation BTKi in CLL: First-Line Treatment With Acalabrutinib or Zanubrutinib


Centering discussion on second-generation BTK inhibitors, expert panelists review clinical data behind first-line acalabrutinib and zanubrutinib, respectively.


Sonali M. Smith, MD: Nicole, ibrutinib is not the only BTK [Bruton tyrosine kinase] inhibitor we have. Can you comment on perhaps the newer ones, how they’re different, and then also tell us a bit about some of the studies that have come out with acalabrutinib?

Nicole Lamanna, MD: Obviously, we have newer covalent BTK inhibitors trying to improve upon some of the toxicity profiles we saw with ibrutinib. We have maturing data on acalabrutinib. We have a follow-up from the ELEVATE-TN study that goes out about 5 years with maturing data now for the newer covalent BTK inhibitors. Of course, we’ll talk I’m sure more about zanubrutinib as well. Again, the efficacy is very good, with high responses. Again, few CRs [complete responses], but the median PFS [progression-free survival] has not been reached. The ELEVATE-TN also looked at the combination of acalabrutinib and obinutuzumab vs acalabrutinib as monotherapy vs chlorambucil and obinutuzumab. These data have shown improvement in overall survival.

The interesting aspect I think about acalabrutinib with the ELEVATE-TN data is the possible contribution of obinutuzumab. Although acalabrutinib plus obinutuzumab and the acalabrutinib arms look very similar, there was no doubt there’s a slight split in the curves, and so interestingly whether the addition of an anti-CD20 monoclonal antibody, particularly obinutuzumab, adds something different than what we saw with some of the rituximab data in addition to ibrutinib. I guess the question I would ask for the panel is, when they’re using acalabrutinib, are they using it with obinutuzumab, given these data? Although again, the median PFS looks great for both the acalabrutinib plus obinutuzumab as well as the acalabrutinib arm in comparison to the obinutuzumab and chlorambucil arm, which is far inferior. I guess the question is, do people use that when they use a BTK?

Sonali M. Smith, MD: I think that’s a great question. Maybe we can quickly ask the panel, do you use obinutuzumab when you are using acalabrutinib?

Sameer A. Parikh, MD: I think in the trials that have compared ibrutinib with or without rituximab, there has been no difference in progression-free survival. It was assumed that even with obinutuzumab along with acalabrutinib, you would see similar results, but there is about a 12 percentage point difference in PFS at 5 years, which is important. One of the challenges in incorporating obinutuzumab with acalabrutinib is that patients need to come in for those infusions. The beauty, if you will, of single-agent acalabrutinib was you can just prescribe it, and patients don’t have to come in for these infusions. I typically will discuss this with my patients. I generally do not use obinutuzumab, but I am increasingly having that conversation. The patient population where I think it should be given are patients who have bulky disease, or where I really need to get a response faster is where I would consider the addition of obinutuzumab.

Sonali M. Smith, MD: Would anybody else like to comment on this?

Ryan W. Jacobs, MD: One other group that I think about using it with is the patients who are having significant autoimmune cytopenias. I do think about an obinutuzumab addition. I had, mostly because of the pandemic, not been reaching for it very often, but thankfully, COVID-19 severity has decreased and we have better treatments. I’m starting to think about it more. There is a poster at ASH [American Society of Hematology annual meeting] this year that’s looking in the real world, do the data match what was seen in the ELEVATE-TN? It seems to mirror what was seen there, so I’ll be thinking about it more.

Sonali M. Smith, MD: I think we’ll move on. Sticking to acalabrutinib for a moment, one of the challenges with the BTK inhibitors in general has been some of the drug-drug interactions. It has to do with the acidic environment that is needed and the contraindication for proton pump inhibitors, in particular with acalabrutinib. Perhaps I’ll ask Ryan if you want to address what might be coming down for everyone?

Ryan W. Jacobs, MD: In the ELEVATE-PLUS trial they were interested in exploring whether they could convert from a capsule to a tablet to work around with acalabrutinib this issue of coadministration with proton pump inhibitors specifically. It was coming up a lot in my clinic, maybe 20% or 25% of my patients it seemed were on proton pump inhibitors, and we would have to think about alternatives to acalabrutinib even if that was what I was wanting to treat them with. In the ELEVATE-PLUS study, they took about 100 patients with the tablet formulation and showed that with the PK [pharmacokinetics] data that it was therapeutic even with the administration of proton pump inhibitors to reassure us that we can use this new tablet formulation even in patients who need those proton pump inhibitors but who we want to treat with acalabrutinib. It’s been very nice to have the tablet formulation.

Sonali M. Smith, MD: It certainly expands the options. Acalabrutinib is not the only second-generation BTK inhibitor. Perhaps I’ll ask John to give us a summary of what’s come through the SEQUOIA trial for zanubrutinib.

John N. Allan, MD: Thank you. Zanubrutinib is the third FDA-approved covalent BTK inhibitor that we have available to us. With that said, it is not FDA approved for chronic lymphocytic leukemia [CLL] at this time but has great data that have been developed, and we expect approval early in 2023 and that it will be available. It is included in the NCCN [National Comprehensive Cancer Network] guidelines as a category-1 option for our patients and is considered a preferred option. Because this is an FDA-approved agent, it is potentially a drug that can be used in the CLL space and has good strong data.

The strong data in the frontline setting come from this very valuable study called SEQUOIA. SEQUOIA was looking at monotherapies and ibrutinib in a randomized 1:1 fashion against bendamustine plus rituximab. This was, in most of these frontline studies, in older patients, greater than 65 with comorbidities. Of interest, they excluded deletion 17p. This is a very large study that has several cohorts where they took the 17p patients and either treated them with continuous therapy of zanubrutinib, or they had another cohort where they had the combination of zanubrutinib and venetoclax. What is important here is the phase 3 portion of this, of the zanubrutinib vs bendamustine and rituximab, which has been published, the primary end point was progression-free survival. Zanubrutinib, which is a selective covalent BTK inhibitor, improves progression-free survival compared to bendamustine and rituximab at the 2-year mark, with about a 15% difference, and has a strongly significant hazard ratio of about 0.4.

This is a valuable agent and in this study showed a very favorable toxicity profile. As a reminder, this is a selective agent similar to acalabrutinib, with a favorable profile in terms of cardiovascular risk factors, etc. No overall survival was noted in this study at this very short follow-up time, but based on these PFS and safety data, it is likely a very valuable drug in the treatment of patients with CLL. Based on this study, it is expected to have approval potentially in 2023 for the frontline therapy of our patients.

Sonali M. Smith, MD: That’s fantastic. Thank you.

Transcript edited for clarity.

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