Safety and activity of the highly specific BTK inhibitor BGB-3111 in combination with the PD-1 inhibitor BGB-A317 in patients with B-cell lymphoid malignancies.

Introduction: BGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC-and EGFR-family kinases, and demonstrates favorable pharmacokinetic and pharmacodynamics properties (Tam et al. ASH 2016). BGB-A317, a humanized IgG4 variant monoclonal antibody with no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor and is being developed for the treatment of solid and hematologic malignancies (Friedlander, ASCO, 2017). The combination of PD-1/PD-L1 inhibitors with B-cell receptor pathway inhibitors is being evaluated in different B-cell malignancies with the expectation of greater benefit for patients. Here, we present early safety data from a Phase 1b trial exploring the combination of BGB-3111 and BGB-A317. Method(s): This is an open-label multicenter, phase study to evaluate safety, tolerability, and preliminary efficacy of BGB-3111 in combination with BGB-A317 in subjects with B-cell malignancies, including Waldenstrom's macroglobulinemia (WM), aggressive and indolent non-Hodgkin's lymphoma, and transformed chronic lymphocytic leukemia/follicular lymphoma (FL) amongst other B-cell malignancies. The study includes a standard 3+3 dose escalation phase followed by dose expansion. The dose levels are: Cohort 1, BGB-3111 320 mg once a day (QD) combined with BGB-A317 2.0 mg/kg every 3 weeks (Q3W); Cohort 2, BGB-3111 320 mg QD combined with BGB-A317 5.0 mg/kg Q3W; and Cohort 3, BGB-3111 160 mg BID combined with BGB-A317 200 mg (flat dose) Q3W. Result(s): As of 01 June 2017, 25 pts were enrolled in the dose escalation portion of the trial: 15 pts in Cohort 1 and 10 pts in Cohort 2. Key patient characteristics, safety, and efficacy are shown in the Table. Safety: Median follow-up was 2.8 (range, 0.4-10.7) months. There were no dose-limiting toxicities (DLTs) in Cohort 1. Cohort 2 saw hemolysis in 2 pts, both with WM; one qualified as a DLT. These events were not associ