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

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 > 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.