Japanese Approval Sought for Valemetostat in Relapsed/Refractory Adult T-Cell Leukemia/Lymphoma

A new drug application seeking the approval of valemetostat tosylate for use in the treatment of patients with relapsed/refractory adult T-cell leukemia/lymphoma has been submitted to the Japanese Ministry of Health, Labour, and Welfare.

A new drug application seeking the approval of valemetostat tosylate (DS-3201b) for use in the treatment of patients with relapsed/refractory adult T-cell leukemia/lymphoma (ATL) has been submitted to the Japanese Ministry of Health, Labour, and Welfare.1

The application is based on data from a pivotal phase 2 trial (NCT04102150) conducted in Japanese patients with 3 aggressive subtypes of relapsed/refractory ATL, which showed that the novel, potent, and selective dual inhibitor of EZH1 and EZH2 had therapeutic efficacy in this population.2

The agent, when delivered at a once-daily dose of 200 mg, elicited an objective response rate (ORR) of 48.0% (95% CI, 30.5%-65.9%) in 25 patients with relapsed/refractory ATL per independent efficacy assessment committee (EAC), meeting the primary end point of the trial. Among those who responded to treatment, the complete response rate was 20.0% (n = 5), the partial response rate was 28.0% (n = 7), and the stable disease rate was 40.0% (n = 10).

At a data cutoff date April 24, 2021, a total of 8 patients were still undergoing treatment. The median duration of response (DOR) had not yet been reached (95% CI, 1.87–not reached). The median time to first response was 1.43 months (range, 1.0-5.6).

“Valemetostat would potentially be the first dual inhibitor of EZH1 and EZH2 to be approved anywhere in the world and couple provide a new type of targeted therapy option for patients with relapsed/refractory ATL, which represents one of the most significant unmet medical needs in Japan,” Wataru Takasaki, PhD, executive officer and head of R&D Division in Japan at Daiichi Sankyo Company, Limited, stated in press release. “Valemetostat is the fifth innovative oncology medicine from our pipeline to be submitted for regulatory approval in Japan in the past 3 years.”

Few effective therapeutic options are available to patients with relapsed/refractory ATL. The ORRs previously reported with agents like mogamulizumab-kpkc (Poteligeo) and lenalidomide (Revlimid) were 50.0% and 42.0%, respectively. The identification of more novel drug targets and the development of additional effective therapies are needed for this patient population.

Overexpression of PRC2 subunits and PRC2 dysfunction is common in ATL cells. Valemetostat was developed to prevent H3K27 trimethylation through inhibition of EZH1 and EZH2 and to permit re-expression of repressed genes.

The open-label, multicenter, single-arm phase 2 trial enrolled 25 patients with ATL who had confirmed HTLV-1 antibodies and who experienced relapse, recurrence, or refraction to standard therapy. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 to 2 and a history of mogamulizumab treatment. If a patient was intolerant to mogamulizumab, they had to have a contraindication following treatment with at least 1 prior therapeutic regimen.

If patients had a prior history of allogeneic hematopoietic stem cell transplantation (HSCT), a history of treatment with EZH inhibitors, or the presence of central nervous system involvement of lymphoma, they were excluded.

Study participants were administered valemetostat orally, at a once-daily dose of 200 mg until disease progression or other criteria for discontinuation were met.

The primary end point of the trial was ORR per independent EAC assessment based on Antitumor Response Assessment Criteria modified for ATL. Key secondary end points included investigator-assessed ORR, best response in tumor lesions, complete remission rate, tumor control rate, time to response, DOR, progression-free survival, overall survival, pharmacokinetics/pharmacodynamics, and safety.

The median age of participants was 69.0 years (range, 59.0-84.0), and 52.0% were female. Moreover, 52.0% of patients had an ECOG performance status of 0, 40.0% had a status of 1, and 8.0% had a status of 2. The median number of prior lines of treatment was 3 (range, 1-8), and 96.0% of patients previously received mogamulizumab. All patients previously underwent HSCT.

Regarding disease subtype, 64.0% of patients had acute disease, 24.0% had lymphoma, and 12.0% had unfavorable chronic disease. Moreover, 32.0% of patients had relapsed disease, 24.0% had recurrent disease, and 44.0% had refractory disease.

Additional data presented during the 2021 ASH Annual Meeting showed that the ORRs achieved with valemetostat in those with acute, lymphoma, and unfavorable chronic disease were 62.5%, 16.7%, and 33.3%, respectively.

Those who had nodal or extranodal lesions experienced an ORR of 50.0% with the agent; the ORRs in those with skin lesions or disease in the peripheral blood were 42.9% and 88.9%, respectively. Additionally, those with relapsed disease achieved an ORR of 37.5%, those with recurrent disease had an ORR of 66.7%, and those with refractory disease had an ORR of 45.5%.

A trend toward a decrease in measurable lesions was observed across all disease sites that were examined. Moreover, a 50% or greater reduction in nodal or extranodal lesions (n = 8/20), skin lesions (n = 3/6), and peripheral blood (n = 8/9) from baseline was reported.

No new safety signals with valemetostat were reported.

All patients experienced treatment-emergent adverse effects (TEAEs) with valemetostat, and 96.0% reported treatment-related AEs (TRAEs). Serious TEAEs were experienced by 32.0% of patients and serious TRAEs were reported in 28.0% of patients. Moreover, grade 3 or higher TEAEs and TRAEs were experienced by 60.0% and 56.0% of patients, respectively.

The most common hematologic toxicities reported with the agent were decreased platelet counts (all grade, 80.0%; grade 3 or higher, 32.0%), anemia (48.0%; 32.0%), decreased neutrophil count (28.0%; 12.0%), decreased lymphocyte count (24.0%; 16.0%), and decreased white blood cell count (20.0%; 12.0%).

The most frequent non-hematologic toxicities included alopecia (all grade, 40.0%), dysgeusia (all grade, 36.0%), decreased appetite (all grade, 20.0%; grade 3 or higher, 8.0%), and pyrexia (all grade, 20.0%).

Two patients each experienced TEAEs and TRAEs that resulted in treatment discontinuation. AEs that required dose interruption or reduction occurred in 20.0% and 8.0% of patients who received valemetostat, respectively. Notably, no treatment-related deaths occurred.


  1. Valemetostat new drug application submitted in Japan for treatment of patients with adult T-cell leukemia/lymphoma. News release. Daiichi Sankyo Company, Limited; December 28, 2021. Accessed January 3, 2022. https://bit.ly/3zjN6Dg
  2. 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. Blood. 2021;138(suppl 1):303. doi:10.1182/blood-2021-146657