EZH2 Inhibitor Valemetostat Shows Antitumor Effect in Hematologic Malignancies

Primary analysis results of a phase 2 study of valemetostat, a selective dual inhibitor of enhancer of zeste homolog 2 (EZH2) and its close homolog (EZH1), showed antitumor activity against hematologic malignancies in patients with relapsed or refractory (R/R) adult T-cell lymphoma/leukemia (ATL).

“EZH2 and 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 ATL can be driven by epigenetic dysregulation,” explained Makoto Yoshimitsu, MD, Kagoshima University Hospital, Japan, and co-authors.

The researchers confirmed EZH2 expression is associated with the development and progression of ATL.

The open-label trial enrolled a total of 25 patients with acute, lymphomatous, or unfavorable chronic ATL subtypes.

The primary endpoint was to evaluate efficacy by central efficacy assessment committee (EAC)-assessed overall response rate (ORR). Secondary outcomes included complete remission (CR) rate, duration of response (DOR), efficacy per investigator assessment, and the safety and pharmacokinetics of valemetostat.

“The median number of prior lines of therapy was 3 (range, 1-8). 24 patients had prior treatment with mogamulizumab. The study met its primary endpoint with a median follow-up of 28 weeks (range, 14-71), valemetostat results in a 48% ORR per EAC assessment (P<.0001; 95% CI, 27.8%-68.7%), including a 20% CR rate,” continued Dr Yoshimitsu and co-researchers.

Further, the DOR was not reached (95% CI, 8.14 weeks-NR). EAC- and investigator-assessed results were reported to be similar.

Grade 3 or higher treatment emergent adverse events (TEAEs) occurred in 15 patients, and severe TEAEs occurred in 6 patients. The most common TEAEs (≥30% of patients) were platelet count decreased (80%), dysgeusia (36%), anemia (48%), and alopecia (40%). No deaths were reported.

“Valemetostat results in a high response rate and durable antitumor effect in Japanese patients 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 in the US, suggesting that valemetostat could be a new treatment option for patients with R/R ATL,” concluded Dr Yoshimitsu, et al.—Alexa Stoia

Yoshimitsu M, Izutsu K, Makita S, et al. 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. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 303.