Pair of Studies Highlight Zanubrutinib Tolerability, Efficacy, Utility

Building on positive results seen at last year’s American Society of Hematology annual meeting, a pair of studies presented at EHA2021 Virtual, this year’s annual meeting of the European Hematology Association, add heft to the advantages of zanubrutinib over other Bruton tyrosine kinase (BTK) inhibitors for several hematologic cancers.

Zanubrutinib is a second-generation BTK inhibitor known to have fewer off-target effects among both treatment-naïve and treatment-experienced patients. It is currently approved for use in patients with mantle cell lymphoma (MCL), while the FDA has accepted a supplemental new drug application (sNDA) for Waldenstrom macroglobulinemia (WM) with a projected Prescription Drug User Fee Act target of October 18, 2021. In addition, zanubrutinib’s sNDA for its use among adults with marginal zone lymphoma (MZL) received a priority review designation in May.

The first study,¹ which took place in China, encompassed 91 patients with a median age of 61 (range, 35-87) years who had relapsed/refractory chronic lymphocytic leukemia (n = 82) or small lymphocytic leukemia (n = 9) (R/R CLL/SLL). Their most common poor prognostic indicators were including unmutated immunoglobulin heavy chain variable region gene(IGHV; 56.0%), del(17p) or TP53 mutation (24.2%), and del(11q) (22%). A high response rate was seen among those with either del(17p) and/or TP53 mutation (91%; (95% CI, 70.8%-98.9%), while all with del(11q) responded (100%; 95% CI, 83.2%-100.0%).

These results add to data previously published from the same trial, which demonstrated that zanubrutinib had a favorable benefit-risk profile.

In the present phase 2 study, patients received 160-mg twice daily zanubrutinib until disease progression or unacceptable toxicity. By the end of the follow-up period (median, 33.9 months [range, 0.8-41.4]), 34.1% of patients had discontinued treatment because of progressive disease or adverse events. However, 66% remained on zanubrutinib.

Overall, 69.2%, 12.1%, and 6.6% had a partial response (PR), PR with lymphocytosis, or complete response, respectively; 3.3% each had stable or progressive disease or discontinued treatment before the first assessment; and 2.2% were not evaluable. In total, 87.9% (95% CI, 79.4%-93.8%) of the entire study cohort had a response.

With additional primary efficacy endpoints of duration of response (DOR) and progression-free survival (PFS), the authors’ analyses revealed:

• 24-month DOR: 83.4% (95% CI, 73.2%-90.0%)
• 36-month DOR: 69.9% (95% CI, 57.0%-79.6%)
• 24-month PFS: 85% (95% CI, 70.5%-87.4%)
• 36-month PFS: 68.1% (95% CI, 56.6%-77.4%)

The most common nonhematologic and hematologic adverse effects (AEs) were upper respiratory tract infection in 56.0% and neutropenia in 78.0%, respectively.

“Deep and durable responses were achieved in all patient subgroups, including patients with high-risk cytogenics,” the authors concluded. “These data support the tolerability of long-term zanubrutinib treatment in R/R CLL/SLL, with no new safety signals identified.”

Results of the second study,² the BGB-3111-215 trial, support using zanubrutinib as a treatment option following previous treatment failure. These preliminary results were seen among 44 patients receiving either 160-mg twice-daily or 320-mg once-daily zanubrutinib following intolerance to the first-generation BTK inhibitors ibrutinib (n = 39) or acalabrutinib (n = 1), with 4 patients having received both. Among this cohort, 34 had CLL, 6 had WM, and 2 each had MCL or MZL. Their median age was 70.5 (range, 49.0-91.0) years, and all received at least 1 zanubrutinib dose post enrollment.

At the November 1, 2020, cutoff, data show that among the 44 patients, 43 were still on treatment. Among those who previously were on ibrutinib or acalabrutinib, 82.8% and 77.8%, respectively, did not have a recurrence of intolerant events, of which there were 87 with ibrutinib and 9 with acalabrutinib. Per patient, this breaks down to a median 2 per (range, 1-5).

Among the patients that did have an intolerant event recur, these were of a lower severity in 86.7% of previous-ibrutinib patients and 50% of previous-acalabrutinib patients.

Following administration of zanubrutinib in the patients, no deaths were reported. However, 77.3% did report an AE (myalagia, 20.5%; confusion, 18.2%; dizziness, 15.9%; fatigue, 15.9%; cough, 11.4%), 13.6% reported a grade > 3 AE, and 2.3%, a serious AE. In addition, 13.6% required dose interruption and 4.5%, dose reduction. No patients required treatment stoppage.

Overall, all patients with efficacy data available maintained (38.5%) or had a deepening (61.5%) response to the newer BTK inhibitor.

“Zanubrutinib provided an additional treatment option after intolerance to other BTK inhibitors,” the authors concluded, “demonstrating tolerability and sustained or improved efficacy.”

Updated results will be presented at a future conference.

References

1. Xu W, Yang S, Zhou K, et al. Zanubrutinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: 34-month follow-up results. Presented at: EHA2021 Virtual; June 9-17, 2021. Abstract EP639. https://library.ehaweb.org/eha/2021/eha2021-virtual-congress/325399/wei.xu.zanubrutinib.monotherapy.in.patients.with.relapsed.or.refractory.html?

2. Shadman M, Sharman JP, Levy MY, et al. Preliminary results of the phase 2 study of zanubrutinib in patients with previously treatment B-cell malignancies intolerant to ibrutinib and/or acalabrutinib. Presented at: EHA2021 Virtual; June 9-17, 2021. Abstract EP642. https://library.ehaweb.org/eha/2021/eha2021-virtual-congress/325402/mazyar.shadman.preliminary.results.of.the.phase.2.study.of.zanubrutinib.in.html?