An open-label, single-arm phase 2 trial of valemetostat for relapsed or refractory adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. This multicenter phase 2 trial (NCT04102150; https://clinicaltrials.gov/ct2/show/NCT04102150; DS3201-A-J201) enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary endpoint was met with a centrally reviewed ORR of 48.0% (90% CI, 30.5% to 65.9%), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL.

Valemetostat Tosilate: First Approval

“…Epigenetic regulators of gene expression are an emerging new target class for cancer therapy, and numerous epigenetic therapies are currently in clinical development [ 1 , 2 ]. Enhancer of zeste homolog 1 and 2 (EZH1 and EZH2) are alternative subunits of polycomb repressive complex 2 (PRC2) and initiate chromatin folding via tri-methylation of the 27th lysine residue of histone H3 (H3K27), resulting in repression of genes associated with tumour suppression and cell differentiation [ 3 – 6 ]. Epigenomic studies of chromatin and transcription regulation have shown that inappropriate H3K27me3 deposition [resulting from a gain-of-function (GOF) mutation of EZH2 and/or overexpression of EZH2] is a key determinant of the abnormal transcriptome and has been implicated in the development and progression of a range of solid tumours and lymphomas, including non-Hodgkin lymphomas (NHL) [ 4 – 6 ].…”

“…Among NHL subtypes, the most rare, aggressive and difficult to treat include adult T-cell leukaemia/lymphoma (ATL) [arises from T cells infected with human T-lymphotropic virus type 1 (HTLV-1)], peripheral T-cell lymphoma (PTCL), and B-cell lymphomas [ 7 ]. First-line treatment for these lymphoma subtypes is multiagent chemotherapy; however, the response to treatment is not durable, relapse is common and the prognosis is generally poor [ 3 , 7 – 9 ]. Thus, there is a need for new treatment options.…”

Valemetostat: First approval as a dual inhibitor of EZH1/2 to treat adult T-cell leukemia/lymphoma

“…Of note, 24 patients that had previous received mogamulizumab treatment had an ORR of 45.8% (complete remission in 4 patients and partial remission in 7) (7). Treatmentemergent adverse events including thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia were manageable and tolerated (7). Larger scale clinical studies are warranted to further investigate the efficacy and safety of valemetostat in the treatment of relapsed or refractory ATL.…”

“…Valemetostat, a dual inhibitor of enhancer of zeste homolog (EZH) 1 and EZH2 developed by Daiichi Sankyo, was approved for treatment of patients with relapsed or refractory ATL in Japan in September 2022 (6). This approval was based on the results of an openlabel, single-arm, phase 2 trial in which 25 patients with relapsed or refractory ATL who had received a median of 3 prior lines of therapy had an overall response rate (ORR) of 48.0%, including complete remission in 5 patients and partial remission in 7 (7). Of note, 24 patients that had previous received mogamulizumab treatment had an ORR of 45.8% (complete remission in 4 patients and partial remission in 7) (7).…”

“…This approval was based on the results of an openlabel, single-arm, phase 2 trial in which 25 patients with relapsed or refractory ATL who had received a median of 3 prior lines of therapy had an overall response rate (ORR) of 48.0%, including complete remission in 5 patients and partial remission in 7 (7). Of note, 24 patients that had previous received mogamulizumab treatment had an ORR of 45.8% (complete remission in 4 patients and partial remission in 7) (7). Treatmentemergent adverse events including thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia were manageable and tolerated (7).…”