Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan & US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platel