Zanubrutinib May Fill the Treatment Gap for CLL With Deletion 17p

Jennifer Brown, MD, PhD

Chronic lymphocytic leukemia (CLL) with deletion 17p is a high-risk patient population for which there remains a clinical need for tolerable therapies that induce lasting responses. Findings from SEQUOIA study subgroup analysis suggest treatment with the selective next-generation Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib (Brukinsa) has the potential to fill the treatment gap.

SEQUOIA is an international, phase 3, open-label, randomized study evaluating zanubrutinib versus bendamustine and rituximab (Rituxan) in treatment-naïve patients with CLL or small lymphocytic lymphoma. The study aims to enroll a total of 710 patients who will be divided into 1 of 6 treatment arms. The primary end points of the study are progression-free survival (PFS), and the secondary end points are overall response rate, overall survival, duration of response, patient-reported outcomes, and the number of patients with adverse events (AEs) and serious AEs.

Results from arm D, which included 36 patients with zanubrutinib in combination with venetoclax (Venclexta) showed that at a median follow-up of 12 months (95% CI, 3.0-21.7), the combination achieved an ORR of 97.2% (95% CI, 85.5%-99.9%). Responses included complete responses in 13.9% of patients, partial responses in 77.8%, and stable disease in 5.6%.

The safety portion of the analysis showed low incidences of diarrhea, neutropenia, and nausea. Overall, the treatment appeared tolerable without cases of tumor lysis syndrome and without the need for dose reductions.

In an interview with Targeted Oncology™, Jennifer Brown, MD, PhD director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, discussed the early analysis of the SEQUOIA trial in patients with treatment-naïve CLL and deletion 17p.

TARGETED ONCOLOGY: Can you explain the need for this clinical trial?

Brown: This SEQOUIA study is a registration trial for zanubrutinib in CLL. And there's a primary analysis focused on patients without 17p deletion comparing single-agent zanubrutinib of single agent continuous therapy to bendamustine/rituximab. There was an RMC with single-agent zanubrutinib for patients with deletion 17p, and what was discussed during ASH talking for the first time is arm D, which is also focused on patients with 17 p deletion, but looking at the combination of zanubrutinib and venetoclax.

So, the goal enrollment is 80 patients, and the study design involves 3 months lead-in with zanubrutinib followed by the addition of venetoclax for 12 to 25 months until disease progression, toxicity, or achievement of undetectable MRD with complete remission.

What key component of the study design would you like other oncologists to know about?

As I mentioned, the patient population is restricted to patients with deletion 17p, which are our highest-risk subgroup in CLL. I think it's particularly important feature of this study because most of the studies that have been done, enrolled CLL patients regardless of prognostic factors. And as a result, there are only often about 10% of patients with deletion 17p enrolled in those studies frontline, which leaves us with maybe 5, 10, or 20 patients to evaluate. It's hard to figure out what the best regimen is for these patients who have the greatest remaining unmet medical need and CLL. So, that's a very important feature of this study, and I think the patient population is representative. They have a high percentage 17p by FISH. They're almost all unmutated for IGVH, and they also mostly have a very complex karyotype, which is something else that goes with 17p.

What results were recently presented from this study?

There were 36 patients evaluable for response. The first response evaluation is after the first 3 months of zanubrutinib. And then there were no response evaluations thereafter. So, the median follow-up is [about] 12 months. The ORR is 97% already, which is quite remarkable, especially given the high-risk patient population, but perhaps not too surprising, because we're combining 2 of our best agents that we have in CLL. So, I think that's quite exciting. Thus far, there's only been 1 progression event, which was a localized progression without disease in other compartments. So that is also relatively good.

The CR rate is 14%, but that's still a moving target because patients need to be evaluated by bone marrow biopsy when they get a CR. And so, there are other patients who potentially qualify who haven't been evaluated by bone marrow biopsy yet

What are the clinical implications of this research?

I think the findings established that the combination of zanubrutinib and venetoclax is safe and preliminarily effective in terms of response rate. We have a lot of such data with ibrutinib/venetoclax, and there are studies pending that look at that with acalabrutinib/ venetoclax. So, those are the other 2 covalent BTK inhibitors in the CLL space. But these are the first data looking at zanubrutinib and venetoclax in terms of safety and efficacy. And so, they're very encouraging in that regard that this combination is safe and well tolerated and highly effective.

What really is going to matter over time, of course, is the durability of remission and the progression-free survival. One big question in the field right now for the 17p-deletion patients is whether it's reasonable to stop their therapy, even if they achieve undetectable MRD. And so, this study has very stringent stopping rules for achievement of undetectable MRD, which is good. And then it will be very interesting to see how the patients do if we can retreat them with zanubrutinib and venetoclax at subsequent relapse, which hopefully will be many years out, because that would be a real benefit potentially compared to staying on therapy. If relapse occurs on therapy, we know there'll be resistant, and we can't retreat them with the same regimen. So, those data are probably still a few years out with any of the drugs, we don't really have that information for ibrutinib/venetoclax yet either.

_Reference:

_{Tedeschi A, Ferrant E, Flinn I, et al. 67 Zanubrutinib in combination with venetoclax for patients with treatment-naïve (TN) chronic lymphocytic leukemia (cll) or small lymphocytic lymphoma (SLL) with del(17p): Early results from arm d of the SEQUOIA (BGB-3111-304) trial. Presented at: 63rd Annual American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 67.}