Long-term treatment with zanubrutinib results in deep and durable responses for the majority of patients with Waldenström macroglobulinemia (WM), according to follow-up efficacy data published in Blood.
Previously published research showed that therapies targeting Bruton’s tyrosine kinase inhibitor (BTK), such as ibrutinib, can yield high response rates among patients with B cell malignancies, including WM; however, off-target activity of less selective BTK inhibitors can lead to high rates of adverse events (AEs).
Zanubrutinib, a selective, potent inhibitor of BTK, has shown less off-target activity against non-BTK kinases than that seen with ibrutinib. In addition, the recommended phase 2 dose of 160 mg twice daily showed high steady-state plasma levels, which resulted in complete and sustained blood and lymph node BTK inhibition.
In a phase 1/2 trial of zanubrutinib (ClinicalTrials.gov Identifier: NCT02343120), investigators evaluated the drug’s safety and efficacy in several B cell malignancies, including WM. The researchers reported the long-term therapy effects among patients with either treatment-naive (TN) or relapsed/refractory (RR) WM.
Overall, 77 patients were included, 24 of whom had TN disease, while 53 had RR disease. The median age was 67 years (range, 40-87), 61 (79%) were men, 74 (96%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. In addition, slightly more than half (40; 51.9%) of patients had both MYD88L265P and CXCR4WT mutations.
The median duration of follow-up was 23.5 months among patients with TN disease and 35.8 months among those with RR WM. The overall response rate was 95.9%, with 100% and 93.9% response rates among patients in the TN group and RR group, respectively.
One patient in the relapsed/refractory group had a complete response. Thirty-two patients overall (43.8%; 8 [33.3%] in the TN group and 24 [49%] in the RR group) had a very good partial response, 27 (37%; 13 [54.2%] in the TN group and 14 [28.6%] in the RR group) had a partial response, and 10 (13.7%; 3 [12.5%] in the TN group and 7 [14.3%] in the RR group) had a minimal response.
Patients with both an MYD88L265P and CXCR4WT mutation had a higher rate of very good partial/complete responses (59%).
All patients had at least 1 treatment-emergent AE; 45 (58.5%) patients had a grade 3 or worse AE, with 5 (6.5%) grade 5 AEs noted (3 from infection).
The 36-month progression-free survival and overall survival rates were 76.2% and 80.2%, respectively.
“As a potent and selective BTK inhibitor, zanubrutinib offers the potential for improved efficacy, safety and tolerability over existing treatment options. To address this question, a randomized phase 3 study comparing the safety and efficacy of zanubrutinib with ibrutinib in patients with WM is underway [ClinicalTrials.gov Identifier: NCT03053440],” the authors concluded.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Trotman J, Opat S, Gottlieb DJ, et al. Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: three years of follow-up. Blood. Published online July 22, 2020. doi:10.1182/blood.2020006449