BTK is critical in B-cell receptor signal transduction, and inhibition of this molecular target is the basis for antitumor activity in several B-cell malignancies. ONO-4059 is a new oral, selective BTK inhibitor that has demonstrated antitumor activity in preclinical models and in pilot clinical studies in patients with CLL that were presented at the 19th Congress of the European Hematology Association (Fegan C, et al. Abstract S705; Kozaki R, et al. Abstract P431).
At the 2014 ASH meeting, Fegan and colleagues presented data from a phase 1 study on pharmacokinetics, safety, and efficacy from 25 heavily pretreated patients with CLL who had a median of 4 previous therapies and were then treated with ONO-4059 at doses ranging from 20 mg to 600 mg daily (Blood. 2014;124. Abstract 3328). Overall, 9 patients had del17p, 6 patients had del11q, 20 patients had unmutated IGVH, and 13 patients had a TP53 mutation.
After a median duration of treatment of 363 days, ONO-4059 was well-tolerated, with grade 1/2 AEs noted in 19 (76%) of the 25 patients. Grade 3/4 dose-independent hematologic AEs were reported in 5 patients, consisting of neutropenia (including 1 patient with febrile neutropenia) and leukopenia. Grade 3 nonhematologic AEs included pyrexia, hepatitis E reactivation, and urinary tract infection. In all, 9 ONO-4059–related serious AEs were reported in 6 patients.
All patients receiving ONO-4059 experienced rapid reductions in lymphadenopathy (83% median reduction in lymph nodes) between treatment cycles 1 and 3, and 72% of the patients had an increase in absolute lymphocyte count. The ORR by International Workshop on CLL (IWCLL) criteria was 84%, including 1 CR, 16 partial remissions (PRs), 4 PRs with lymphocytosis, and 1 patient with stable disease. Moreover, there was an 89% ORR to ONO-4059 in patients with del17p. These encouraging results will prompt further assessment of ONO-4059 in patients with relapsed or refractory CLL with del17p who have a poor prognosis.
