Valemetostat for Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results from a Phase 1 Trial
Authors: Jacobsen Eric , Maruyama Dai , Porcu Pierluigi , Tobinai Kensei , Allen Pamela B. , Ishitsuka Kenji , Tsukasaki Kunihiro , Kusumoto Shigeru , Foss Francine M. , Yamauchi Nobuhiko , Morishima Satoko , Imaizumi Yoshitaka , Izutsu Koji , Feldman Tatyana , Kawamata Toyotaka , Kakurai Yasuyuki , Yamauchi Hideyuki , Biserna Noha , Inoue Ai , Tsutsumi Shinji , Horwitz Steven M. 
Published: December 2023

Introduction: Treatment (Tx) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited and prognosis is too often poor for patients (pts) with relapsed or refractory (R/R) disease. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional profile is broadly associated with gene silencing.
Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that prevents H3K27me3 and increases expression of genes involved in immune function ( SLA, PAG1) that can be silenced by H3K27me3. Valemetostat was approved in Japan for the Tx of R/R adult T-cell leukemia/lymphoma (ATLL) in 2022.
The clinical activity of valemetostat in pts with R/R NHLs was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary outcomes for pts in J101 with R/R T-NHLs treated with valemetostat.
Methods: This open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were ≥ 18 (US) or ≥ 20 (Japan) years (y) of age and relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation phase (Japan only) followed by a dose-expansion phase (Japan & US). Enrollment in the expansion phase was limited to pts with R/R peripheral T-cell lymphoma (PTCL) or ATLL. Pts received valemetostat once daily in continuous 28-day (d) Tx cycles at 150-300 mg/d in the escalation phase and 200 mg/d in the expansion phase until disease progression or intolerance.
Key endpoints for the dose-escalation and dose-expansion cohorts were safety and PK parameters. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). DOR and PFS were estimated using Kaplan-Meier methods. Results for PTCL and ATLL are reported separately.
Results: At the primary data cutoff (Dec 31, 2022), 71 pts were included in the efficacy and safety analyses; 57 with PTCL and 14 with ATLL. Median age at baseline was 68.0 (range 26-83) y in the PTCL group and 66.5 (37-78) y in the ATLL group, and median prior therapies were 2.0 (1-8) and 2.5 (1-8), respectively; 16 (28%; 14 autologous, 2 allogeneic) pts with PTCL and 2 (14%, both allogeneic) with ATLL had previously undergone transplant. The most common PTCL subtypes were PTCL, not otherwise specified (PTCL, NOS; n = 26, 46%) and angioimmunoblastic T-cell lymphoma (AITL; n = 23, 40%). Tx was ongoing for 8 (11%) pts at data cutoff.
All 71 pts included at data cutoff experienced ≥ 1 Tx-emergent adverse event; 59 (83%) pts had a Tx-related adverse event (TRAE). The most common all-grade TRAEs were cytopenias, dysgeusia, and alopecia; the most frequent grade ≥ 3 TRAEs were decreased neutrophil (17%), lymphocyte (11%), and platelet (14%) counts ( Table 1). TRAEs led to Tx discontinuation for 4 (6%) pts (1 each: acute myeloid leukemia, myelodysplastic syndrome, colitis, and acute kidney injury), dose reduction for 5 (7%) pts, and Tx interruption for 18 (25%) pts.
The ORR was 55% (30/55) in the PTCL group and 64% (9/14) in the ATLL group, with CR rates of 31% (17/55) and 29% (4/14), respectively; within the PTCL group, the ORR among evaluable pts was 50% (13/26) for PTCL, NOS and 64% (14/22) for AITL ( Table 2). Median times to response were 1.8 (range 1.0-5.6) months (mo) in the PTCL group and 1.9 (1.7-19.4) mo in the ATLL group. Median DOR was 21.9 mo (95% confidence interval [CI], 10.2 mo to not reached [NR]) in the PTCL group (median follow-up 16.4 mo) and 21.2 (95% CI, 1.4 to 38.7) mo in the ATLL group (median follow-up 23.0 mo). Median PFS was 7.7 and 4.1 mo, respectively (median follow-up 18.2 mo and NR).
Conclusions: Valemetostat was well tolerated and showed encouraging clinical activity in pts with R/R T-NHLs. Cytopenias were common but could usually be managed without Tx discontinuation. Valemetostat induced durable responses, with median DOR of &gt; 1.5 y in both the PTCL and ATLL groups. Results for pts in this trial with R/R B-NHLs (Izutsu et al) and from a phase 2 trial in R/R T-NHLs (Horwitz et al) are reported separately.