Background: Tazemetostat is a selective, reversible, small-molecule inhibitor of enhancer of zest homolog 2 (EZH2), a histone methyltransferase. EZH2 is the catalytic subunit of polycomb repressive complex 2, which methylates lysine 27 on histone 3 (H3K27). Recurrent gain-of-function alterations in EZH2 occur in approximately 30% of germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) and 27% of follicular lymphoma (FL). The aim of this multicenter, open-label, Phase 2 study was to assess the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory B-cell Non-Hodgkin's Lymphoma (NHL) harboring the EZH2 mutation. Methods: Patients with histologically diagnosed FL (cohort 1) or DLBCL (cohort 2) were screened centrally for EZH2 mutation using the cobas EZH2 Mutation Test. Tazemetostat (800 mg BID) was administered orally for 28 days/cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) based on IWG-2007 by independent imaging review and safety was evaluated as the secondary endpoint. Results: Among the 20 eligible patients, 17 were enrolled in cohort 1, and 3 were enrolled in cohort 2. In cohort 1, the median number of prior chemotherapy was 2 (range 1-4) and the ORR was 76.5% , including 6 patients (35.3%) achieving a complete response and 7 patients (41.2%) achieving a partial response (PR) as of the data cutoff. The ORR in subjects who received prior treatment with bendamustine, rituximab, and CHOP was 87.5%, 76.9%, and 76.9%, respectively. All 3 patients in cohort 2 (100%) achieved PR. In cohort 1, 3 of the 17 subjects (17.6%) had progression-free survival (PFS) events. The median PFS was not reached. Estimated PFS rates at 12 and 15 months based on the Kaplan-Meier analysis were 94.1% and 73.2%, respectively. The median duration of response (DOR) was not reached, and the DOR rate at 9 and 12 months was 100% and 80.0%, respectively. The median time to response was 3.6 months. The most common grade-3 treatment emergent adverse event (TEAE) was lymphopenia (2 patients, 10.0%). Grade-4 TEAEs included hypertriglyceridemia and pneumonia aspiration (1 patient each, 5.0%). TEAEs leading to study drug discontinuation were reported by 4 of 20 (20.0%) patients, including fatigue (2 patients, 10.0%), atypical pneumonia, traumatic intracranial haemorrhage, non-small cell lung cancer, muscle spasticity, and dysgeusia (1 patient each, 5.0%), indicating that the safety profile was acceptable and manageable. Conclusion: Tazemetostat at a dose of 800 mg BID showed encouraging efficacy in patients with relapsed or refractory EZH2 mutation-positive FL with an acceptable safety profile in the overall population. Thus, tazemetostat may be a potential option for the treatment of relapsed or refractory EZH2 mutation-positive FL.

Citation Format: Shinya Rai, Kiyoshi Ando, Akifumi Takaori-Kondo, Hirohiko Shibayama, Takanori Teshima, Junya Kuroda, Koji Kato, Yoshitaka Imaizumi, Kisato Nosaka, Rika Sakai, Tadashi Nakanishi, Seiichiro Hojo, Koji Izutsu. Phase 2 study of tazemetostat in Japanese patients with relapsed or refractory EZH2 mutation-positive B-cell Non-Hodgkin's Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT176.