On August 31, 2021, the Bruton’s tyrosine kinase inhibitor zanubrutinib was approved for treatment of adults with Waldenström’s macroglobulinemia.1
Supporting Efficacy Data
Approval was based on findings in patients receiving zanubrutinib in the phase III open-label ASPEN trial (ClinicalTrials.gov identifier NCT03053440).1 In cohort 1, 201 patients with MYD88 L265P mutation were randomly assigned to receive oral zanubrutinib at 160 mg twice daily (n = 102) or ibrutinib at 420 mg once daily (n = 99) until disease progression or unacceptable toxicity. In cohort 2, 26 patients with wild-type MYD88 and 2 with unknown MYD88 status received zanubrutinib at 160 mg twice daily.
On independent review committee assessment, partial response or better was observed in 79 of 102 patients given zanubrutinib in cohort 1 (77.5%, 95% confidence interval [CI] = 68.1%–85.1%). The event-free duration of response at 12 months was 94.4% (95% CI = 85.8%–97.9%). In cohort 2, partial response or better was observed in 13 of 26 evaluable patients (50.0%, 95% CI = 29.9%–70.1%).
How It Is Used
The recommended zanubrutinib dosage for this indication is 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity. The recommended dose for patients with severe hepatic impairment is 80 mg twice daily.
Product labeling provides instructions on dosage modification, including dose reduction, for hematologic toxicities and grade 3 or 4 nonhematologic toxicities. Labeling provides information on concomitant use with moderate and strong CYP3A inhibitors and moderate and strong CYP3A inducers.
Among patients receiving zanubrutinib in ASPEN cohort 1, the most common adverse events of any grade including laboratory abnormalities (≥ 25%) were decreased neutrophil count (50%), increased glucose (45%), musculoskeletal pain (45%), upper respiratory tract infection (44%), hemorrhage (42%), decreased platelet count (35%), fatigue (31%), increased creatinine (31%), rash (29%), and decreased calcium (27%). The most common grade 3 or 4 adverse events included musculoskeletal pain (9%); hypertension (9%); and pneumonia, pyrexia, and hemorrhage (4% each). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (24%), platelets (8%), and hemoglobin (7%).
Serious adverse events occurred in 44% of patients in cohort 1, most commonly pneumonia and hemorrhage (4% each), as well as in 39% of patients in cohort 2, most commonly pneumonia (14%). Adverse events led to treatment discontinuation in 2% of cohort 1 (including hemorrhage in one patient and neutropenia in one patient) and in 7% of cohort 2 (including subdural hemorrhage in one patient and diarrhea in one patient).
Zanubrutinib has warnings/precautions for hemorrhage; infections; cytopenia; second primary malignancies (including skin cancers); cardiac arrhythmia; and embryofetal toxicity. Patients should be advised not to breastfeed while receiving zanubrutinib.
1. Brukinsa (zanubrutinib) capsules prescribing information, BeiGene,
August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213217Orig1s004lbl.pdf. Accessed September 7, 2021.