Pair of studies demonstrate safety, efficacy and usefulness of zanubrutinib

The first study,1 which took place in China, included 91 patients with a median age of 61 (range, 35-87) years who had relapsed / refractory chronic lymphocytic leukemia (n = 82) or small lymphoid leukemia (n = 9) ( R / R CLL / SLL). Their most common indicators of poor prognosis included the 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 observed in people with a del (17p) and / or TP53 mutation (91%; (95% CI: 70.8% -98.9%), while all people with del (11q) responded (100%; 95% CI, 83.2% -100.0%).

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

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

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

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

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

The most common non-haematologic and hematologic adverse reactions (AEs) were upper respiratory tract infection in 56.0% and neutropenia in 78.0%, respectively.

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

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

As of November 1, 2020, data shows that among the 44 patients, 43 were still on treatment. Of those previously taking ibrutinib or acalabrutinib, 82.8% and 77.8%, respectively, did not have a recurrence of intolerant events, including 87 with ibrutinib and 9 with acalabrutinib. Per patient, this breaks down into a median of 2 per (range, 1-5).

Among the patients who had a recurrent intolerant event, these were of lower severity in 86.7% of the patients who had previously received ibrutinib and 50% of the patients who had previously received acalabrutinib.

After administration of zanubrutinib to patients, no deaths have been reported. However, 77.3% reported an AE (myalagia, 20.5%; confusion, 18.2%; dizziness, 15.9%; fatigue, 15.9%; cough, 11.4%), 13.6 % reported a grade > 3 AEs, and 2.3%, a serious AE. Additionally, 13.6% required a dose interruption and 4.5% a dose reduction. No patient required discontinuation of treatment.

Overall, all patients for which efficacy data were available maintained (38.5%) or had a more profound response (61.5%) to the new BTK inhibitor.

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

The updated results will be presented at a future conference.

The references

1. Xu W, Yang S, Zhou K, et al. Zanubrutinib as monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: follow-up results at 34 months. Presented at: EHA2021 Virtual; June 9-17, 2021. Abstract EP639.

2. Shadman M, Sharman JP, Levy MY, et al. Preliminary results of the phase 2 study of zanubrutinib in patients previously treated for malignant B cell tumors intolerant to ibrutinib and / or acalabrutinib. Presented at: EHA2021 Virtual; June 9-17, 2021. Abstract EP642.

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