BGB-3111 Induces Robust Response in Waldenstrom Macroglobulinemia

BGB-3111, a highly specific BTK inhibitor, is active in patients with Waldenström macroglobulinemia (WM), according to an interim analysis from an ongoing phase I trial presented at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland.

With a median follow-up of 12.3 months, 42 patients in the efficacy population demonstrated a best objective response rate (ORR) of 90%. Although no complete response was reported, 18 (43%) patients showed very good partial response (VGPR), 14 (33%) patients achieved partial response (PR), and 6 (14%) patients showed minor response (MR). Stable disease was demonstrated by the remaining 4 (10%) patients.

The 1-year progression-free survival rate was 91.7% with BGB-3111. Median time to response was 28 days.

Median trough occupancy of BTK in patients was 100% at 160 mg twice daily versus 94% at 320 mg of once daily BGB-311 (P = .002).

WM is a B-cell malignancy that is characterized by characterized by large amounts of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. A hallmark of WM is constitutive activation of the BTK, a critical signaling component of the B-cell receptor and a key mediator of cell survival.

Judith Trotman, MBChB, clinical associate professor clinical associate professor of hematology at Concord Repatriation General Hospital in Concord, Australia, explained that modified WM response criteria were used in this trial that defines VGPR as ≥90 reduction of serum IgM from baseline and a reduction of lymphadenopathy or splenomegaly (if present), and MR as at least 25% but less than 50% reduction of serum IgM from baseline.

“BGB-311 has been shown to be equipotent to ibrutinib in cellular assays.” Trotman said. “BGB-3111 achieves high plasma concentrations and complete BTK occupancy in blood and lymph nodes that results in a high very good response rate in patients with WM.

“While the first generation BTK inhibitor, ibrutinib, has shown clinical benefit in WM, it also delivers significant side effects of bruising, bleeding, diarrhea, and cardiac arrhythmias.”

BGB-3111 has been designed to minimize off target inhibition of other kinases, including EGFR, ITK, JAK3, HER2, and TEC, with the aim of decreasing these side effects.

This phase I dose escalation trial enrolled 48 patients with WM who had received one or more prior therapies (range, 0-8), ECOG PS of 0 to 2, and had no available treatment option. The median patient age was 66 (range, 44-87) years.

BGB-3111 was administered orally at 40 mg, 50 mg, and 100 mg daily. Patients then went into the dose expansion phase and received the recommended phase 2 dose of 320 mg daily or 160 mg twice daily.

The median reduction of IgM from baseline was 32.7 g/L (81.3%) and a computed tomography detected a 45.5% median reduction of lymphadenopathy.

Patients presenting with serum hemoglobin levels <10 g/dL at baseline demonstrated an increase in hemoglobin from a median of 8.8 g/dL (range, 7.1-9.8) to 13.8 g/dL (range, 10.7-16.1) following BGB-3111 treatment.

“BGB-311 was very well tolerated,” Trotman said. “To date, there have been no treatment-related discontinuations due to BGB-3111 toxicity, although one patient in VGPR died due to pre-existing bronchiectasis.”

The most common grade 1/2 adverse events (AEs) reported in ≥20% of patients included upper respiratory infection (31%), petechiae/purpura/contusion (28%), and constipation (25%). There were 3 treatment-related AEs reported: atrial fibrillation and headache, both grade 2; and 1 grade 3 cryptococcal meningitis. All 3 cases resolved following withdrawal of BGB-3111, which was then safely resumed. Atrial fibrillation (one grade 1 and two grade 2) occurred in 3 patients and one patient had developed grade 3 diarrhea.

There were no cases of serious hemorrhage reported.

Trotman J, Opat S, Marlton P, et al. Bruton's tyrosine kinase (BTK) inhibitor BGB-3111 demonstrates high very good partial response (VGPR) rate in patients with Waldenström macroglobulinemia (WM). Hematol Oncol. [published online June 7, 2017] 35, 2017. (suppl S2; abst 059). doi: 10.1002/hon.2437_58.