Valemetostat Tosilate Approved in Japan for R/R PTCL

Valemetostat tosilate (Ezharmia), a first-in-class dual EZH1 and EZH2 inhibitor, has been approved by the Japan Ministry of Health, Labor and Welfare (MHLW) for the treatment of adult patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).¹

This regulatory decision was based on findings from the global, open-label, single-arm, 2-cohort phase 2 VALENTINE-PTCL01 trial (NCT04703192). Findings presented at the 2023 ASH Annual Meeting showed that treatment with valemetostat tosilate led to an overall response rate (ORR) of 43.7% (95% CI, 34.6%-53.1%) among 119 efficacy-evaluable patients with relapsed/refractory PTCL. Seventeen patients achieved complete response (CR), and 35 patients achieved partial response (PR). Responses were observed across several PTCL subtypes, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified.

“This second indication for [valemetostat tosilate] in Japan is an important advance for the treatment of relapsed or refractory PTCL, as new and effective treatment options are needed to improve patient outcomes,” Toshinori Agatsuma, PhD, executive officer and head of the R&D Division of Daiichi Sankyo in Japan, stated in a news release. “[Valemetostat tosilate] exemplifies the innovative research being conducted by Daiichi Sankyo aimed at creating new medicines with potential to change the standard of care for patients with cancer.”

VALENTINE-PTCL01 enrolled adult patients at several sites across Asia, Europe, North America, and Oceania with relapsed/refractory PTCL and adult T-cell leukemia/lymphoma (ATL) who had received 1 or more prior systemic therapies and were ineligible for hematopoietic stem cell transplant at the time of screening. Cohort 1 included patients with PTCL, and Cohort 2 enrolled those with ATL.²

Patients were eligible if they had an ECOG performance status of 0 to 1; at least 1 measurable lesion; and documented relapsed, refractory, or progressive disease after at least 1 prior line of systemic therapy for PTCL or ATL.

Patients were excluded from enrollment if they had a diagnosis of mycosis fungoides, Sézary syndrome, and primary cutaneous anaplastic large cell lymphoma (ALCL), or systemic dissemination of primary cutaneous ALCL; a diagnosis of precursor T-cell leukemia and lymphoma, T-cell prolymphocytic leukemia, or T-cell large granular lymphocytic leukemia; a prior malignancy active within the previous 2 years, except for locally curable cancer that is currently considered cured; lymphoma with active central nervous system involvement; a history of autologous hematopoietic cell transplant within 60 or 90 days prior to the first dose of the study drug; clinically significant graft-vs-host disease (GVHD) or GVHD requiring systemic immunosuppressive prophylaxis or treatment; an inadequate washout period from prior lymphoma-directed therapy before enrollment; uncontrolled or significant cardiovascular disease; a history of treatment with other EZH inhibitors; current use of moderate or strong CYP3A inducers; systemic treatment with corticosteroids; or known or suspected hypersensitivity to valemetostat tosilate or any of its excipients.

Patients in cohort 1 received valemetostat tosilate orally at 200 mg once daily starting on day 1 of cycle 1 until disease progression or unacceptable toxicity.

The primary end point was ORR per CT-based blinded independent central review (BICR). Key secondary end points included duration of response, CR rate, PR rate, duration of CR, and progression-free survival, all assessed by BICR and the investigators. Other secondary end points included investigator-assessed ORR, overall survival, safety, and pharmacokinetics. Exploratory end points included biomarker mutational status and PET-CT–based BICR.

In VALENTINE-PTCL01, the safety profile of valemetostat tosilate was shown to be consistent with that reported in prior clinical trials.1 In total, 79.7% of 133 safety-evaluable patients had treatment-related adverse effects, the most common being decreased platelet counts (44.4%), anemia (27.1%), and decreased neutrophil counts (21.1%).

Previously, in 2022, Japan’s MHLW approved valemetostat tosilate for the treatment of patients with relapsed/refractory ATL based on findings from a pivotal phase 2 trial (NCT04102150).³

References

1. Ezharmia approved in Japan as first dual EZH1 and EZH2 inhibitor therapy for patients with peripheral T-cell lymphoma. News release. Daiichi-Sankyo. June 24, 2024. Accessed June 24, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202406/20240624_E2.pdf
2. Valemetostat tosylate (DS-3201b), an enhancer of zeste homolog (EZH) 1/2 dual inhibitor, for relapsed/refractory peripheral T-cell lymphoma (VALENTINE-PTCL01). ClinicalTrials.gov. Updated April 15, 2024. Accessed June 24, 2024. https://clinicaltrials.gov/study/NCT04703192
3. Ezharmia approved in Japan as first dual EZH1 and EZH2 inhibitor therapy for patients with adult T-cell leukemia/lymphoma. News release. Daiichi Sankyo. September 26, 2022. Accessed June 24, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202209/20220926_E.pdf