Extended Follow-Up Data on Tirabrutinib in Treatment-Naïve and Relapsed/Refractory Waldenström Macroglobulinemia

Second-generation oral Bruton tyrosine kinase (BTK) inhibitor tirabrutinib demonstrated sustained efficacy in treatment-naïve (TN) and relapsed/refractory (R/R) Waldenström’s macroglobulinemia (WM), according to two-year follow-up data from a phase II study presented at the 2021 American Society of Hematology Annual Meeting.

Tirabrutinib, designed to improve the safety and efficacy of ibrutinib with a more favorable toxicity profile, was approved in Japan in 2020 for TN or R/R WM. Results from an open-label, prospective, single-arm phase II study conducted at 19 facilities in Japan, previously reported with data cutoff on August 28, 2019, provided the basis for this approval.

The present report details results from a phase II study that enrolled 18 patients with TN WM and nine with R/R WM. Major response rate (MRR) as assessed by an independent review committee (IRC). Secondary endpoints were overall response rate (ORR), time to major response (TTMR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Participants with serum IgM ≥500 mg/dL received tirabrutinib 480 mg under fasting conditions once daily until disease progression or unacceptable toxicity.

Median follow-up was 23.8 months in the TN cohort and 25.4 months in the R/R arm. A total of five patients discontinued treatment because of adverse events (AEs), including atypical mycobacterial infection (n = 1), progressive disease (n = 1), physician’s discretion (n = 1), and withdrawal by subject (n = 2). MRR assessed by IRC was 94.4% in the TN group and 88.9% in the R/R group.

IRC-assessed ORR was 94.4% in the TN arm and 100% in the R/R cohort. In both cohorts, the rate of very good partial response or greater was 33.3%. In the TN group, median TTMR was 1.9 months (range = 1-20.3) compared with 2.1 months (range = 1-3.7) in the R/R arm. Across both treatment groups, median PFS, OS, and DOR were not reached. The two-year PFS rates were 94.4% and 88.9% in the TN and R/R cohorts, respectively. In patients who remained on treatment, continued reductions in IgM were observed.

Across both treatment groups, the most common AEs were rash (44.4%), neutropenia (33.3%), and nasopharyngitis (25.9%). The most common grade ≥3 AEs were neutropenia (22.2%), lymphopenia (18.5%), and leukopenia (11.1%). One new grade ≥3 treatment-related AE of hypertriglyceridemia was observed during the follow-up period.