Bruton's tyrosine kinase (BTK) inhibitor BGB-3111 demonstrates high very good partial response (VGPR) rate in patients with Waldenstrom macroglobulinemia (WM).

Introduction: BTK inhibitors have been shown to be highly active in WM, particularly WM harboring a MYD88 mutation (MYD88MUT). BGB-3111 is a potent, specific, and irreversible BTK inhibitor. In primary patient (pt) samples, BGB-3111 demonstrated profound BTK inhibition with minimal inhibition of off-target kinases such as EGFR, ITK, JAK3, HER2, and TEC. In phase 1 testing, high plasma concentrations were safely achieved, resulting in complete, sustained BTK inhibition in blood and lymph nodes. Method(s): This was an open-label, multicenter, dose-finding phase 1 study of BGB-3111 in pts with B-cell malignancies, with indicationspecific expansion cohorts. Here, updated safety and efficacy in WM are reported. Result(s): As of 31 Dec 2016, 46 pts with WM were enrolled: median 2 prior therapies (range 0-8), median follow-up 8.2 months (1.4-28), 46 evaluable for safety, 41 for efficacy; 5 non-evaluable pts had either baseline IgM <500 mg/dL (n = 3) recent plasmapheresis (n = 1) or <12 weeks' follow-up (n = 1). The most frequent adverse events (>=20%, all grade [Gr] 1 or 2) were upper respiratory infection (33%), contusion (28%), and constipation (22%). There were 3 treatment-related serious adverse events (Gr 2 atrial fibrillation [AF], Gr 2 headache, Gr 3 cryptococcal meningitis); in all 3 cases, BGB-3111 was withheld and safely resumed. 3 pts developed AF (one Gr 1, two Gr 2), and 1 developed Gr 3 diarrhea. No serious hemorrhage was reported. The objective response rate was 93% (38/41), with a major response rate of 78% (32/41): VGPR in 39% (16/41) and PR in 39% (16/41). Median time to response was 28 days. Response by MYD88 and CXCR4 mutational status, in pts with known status (n = 32) is shown in Table 1. In pts with hemoglobin <10 g/dL at baseline, hemoglobin increased from a median of 8.8 g/dL (7.1-9.8) to 13.8 g/dL (10.7-16.1). IgM decreased from a median of 32.5 g/ L (6-88.5) at baseline to 5.4 g/L (0.4-47.8).16 pts with baseline lymphadenopathy had a median reduc