Clinical development of BTK inhibitors in Japan

Abstract

The current status of clinical development of Bruton's tyrosine kinase (BTK) inhibitors in Japan will be summarized. BTK is an essential kinase in the B‐cell receptor signaling pathway playing an important role in the pathogenesis of several B‐cell malignancies, including MCL, CLL/SLL, FL and MZL. A phase I study of ibrutinib, an oral covalent BTK inhibitor, in Japanese patients (pts) with relapsed/refractory (r/r) B‐cell malignancies was conducted. Fifteen pts were enrolled to one of 3 cohorts. Cohort 1 (n=3) consisted of single‐dose (140 and 280 mg) phase and a multiple‐dose (420 mg) phase, cohort 2 (n=6) included multiple doses of 560 mg, and cohort 3 (n=6) included only pts with CLL/SLL dosed at ibrutinib 420 mg. The most common adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin and rash. Dose dependent increase in maximum plasma concentration and area under the concentration was observed. The overall response rate was 73% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable toxicity profiles and effective for Japanese pts with r/r B‐cell malignancies including CLL/SLL (Int J Hematol 2016;103:86‐94). Subsequently, the following clinical trials of ibrutinib have been conducted in Japan; 1) phase II study for r/r MCL, 2) phase III study with rituximab plus bendamustine (RB) for untreated MCL, 3) phase III study with RB for r/r FL, 4) phase III study with R‐CHOP for untreated non‐GCB DLBCL. ONO/GS‐4059 is a selective and an irreversible inhibitor of BTK. Phase I study of ONO/GS‐4059 was conducted for 90 pts with r/r B‐cell malignancies in UK and France, showing promising safety and efficacy results (Blood 2016;127:411‐9). Phase I study of ONO/GS‐4059 has also been conducted in Japan, showing promising results. BTK inhibitors will be important tools for the future management of various B‐cell malignancies.