Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

Background: Enhancer of zeste homolog 2 (EZH2) and its close homolog, EZH1, catalyze the attachment of 3 methyl groups to histone H3 at lysine 27 (H3K27me3). H3K27me3 is an epigenetic mark involved in downregulating gene expression associated with tumor suppression and cell differentiation. Recent evidence suggests that adult T-cell leukemia/lymphoma (ATL) can be driven by epigenetic dysregulation (Blood. 2016;127:1790-1802). Specifically, altered EZH2 expression has been implicated in the development and progression of ATL. Valemetostat tosylate (DS-3201b; valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that has demonstrated antitumor activity against hematologic malignancies, especially T-cell lymphoma, including relapsed or refractory (R/R) ATL in a phase 1 study (EHA 2021. Abstract S218). Here, we report the results from the primary analysis of a pivotal phase 2 study of valemetostat in Japanese patients (pts) with R/R ATL.

Aims: This multicenter, single-arm, open-label, phase 2 study (NCT04102150) evaluated the efficacy and safety of single-agent valemetostat in pts with R/R ATL. The primary objective was to evaluate efficacy by central efficacy assessment committee (EAC)–assessed overall response rate (ORR), defined as the proportion of pts whose best response was complete remission (CR), uncertified CR, or partial remission using international consensus criteria (J Clin Oncol. 2009;27:453-59). The null hypothesis was an ORR of ≤5% (binomial test with a 1-sided significance level of 5%). Secondary outcome measures included CR rate, duration of response (DOR) per EAC, efficacy per investigator (INV) assessment, and the safety and pharmacokinetics of valemetostat.

Methods: Pts ≥20 years of age with R/R ATL (acute, lymphomatous, or unfavorable chronic type) were enrolled from 24 sites in Japan. Pts must have had a positive antihuman T-cell leukemia virus type 1 antibody serum test and received prior therapy with mogamulizumab or ≥1 prior systemic therapy in the case of intolerance of, or contraindication for, mogamulizumab. Pts with prior allogeneic hematopoietic stem cell transplant were excluded. Valemetostat 200 mg was orally administered once daily in continuous 28-day cycles until disease progression or intolerance. The EAC-determined efficacy assessment was based on central evaluation of radiographic images and clinical data, including peripheral blood, skin, and bone marrow lesions (J Clin Oncol. 2009;27:453-59).

Results: At the time of data cutoff (April 24, 2021), the study enrolled the planned 25 pts which included 16, 6, and 3 pts with acute, lymphomatous, or unfavorable chronic ATL subtypes, respectively. The median age was 69 years (range, 59-84 years). The median number of prior lines of therapy was 3 (range, 1-8). 24 pts (96.0%) had prior treatment with mogamulizumab.

The study met its primary endpoint: with a median follow-up of 28 weeks (range, 14-71 weeks), valemetostat resulted in a 48% (12/25) ORR per EAC assessment (P<.0001; 95% CI, 27.8%-68.7%), including a 20% CR rate. Primary efficacy data are summarized in the Table. The median DOR (n=12) was not reached (95% CI, 8.14 weeks-not reached). EAC- and INV-assessed results were similar.

8 of 25 pts (32%) remained on treatment. 25 pts (100%) experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 15 pts (60%), and grade ≥3 serious TEAEs occurred in 6 pts (24%); valemetostat was not associated with any deaths. Dose interruption or reduction due to TEAEs occurred in 5 (20%) and 2 (8%) pts, respectively. Two pts (8%) discontinued due to TEAEs. The most common TEAEs (≥30% of pts) were platelet count decreased (80%), dysgeusia (36%), anemia (48%), and alopecia (40%); grade ≥4 platelet count decreased occurred in 3 pts (12%).

Summary/Conclusions: Valemetostat resulted in a high response rate and durable antitumor effect in Japanese pts with R/R ATL, the majority of whom were pretreated with mogamulizumab. Valemetostat’s safety profile was manageable. These results are consistent with those observed in the phase 1 study conducted in Japan and the US, suggesting that valemetostat could be a new treatment option for pts with R/R ATL. Valemetostat is also being evaluated in a global phase 2 study in pts with R/R ATL and R/R peripheral T-cell lymphoma (NCT04703192).