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 enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), 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 to NR; months). 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. This trial was registered at www.clinicaltrials.gov as #NCT04102150.

Conflict of interest statement

Conflict-of-interest disclosure: K. Izutsu has received honoraria from Eisai, Chugai, Janssen, AstraZeneca, Novartis, Bristol Myers Squibb, Kyowa Kirin, AbbVie, Ono Pharmaceutical, Eli Lilly, MSD, Daiichi Sankyo, Symbio, and Takeda; research funding from Eisai, Chugai, Janssen, AstraZeneca, Novartis, AbbVie, Daiichi Sankyo, Pfizer, Yakult, Genmab, Beigene, and Incyte; and has had an advisory or consulting role with Eisai, AbbVie, and Genmab. S. Makita has received honoraria from Celgene/Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo/UCB Japan, Eisai, Novartis, Takeda, CSL Behring, and Meiji Seika Pharma and has had an advisory or consulting role at Celgene/Bristol Myers Squibb and Takeda. M.Y. has received honoraria from Takeda, Bristol Myers Squibb/Medarex, Novartis, CSL Behring, Chugai Pharma, Otsuka, and Daiichi Sankyo and has had an advisory or consulting role at Takeda. A.U. has received honoraria from Bristol Myers Squibb and Meiji Seika Pharma and has had an advisory or consulting role with JIMRO and Otsuka Medical Devices. S.K. has received honoraria and research funding from Chugai Pharmaceutical Co Ltd, Kyowa Kirin Co Ltd, and Daiichi Sankyo/UCB Japan. S. Morishima has received honoraria from Pfizer, Janssen, AbbVie, Nippon Shinyaku, Bayer, Chugai Pharma, Sanofi, Kyowa Kirin, Takeda, and Daiichi Sankyo. K. Tsukasaki has received honoraria from Chugai Pharmaceutical Co Ltd/Roche, Eisai, Kyowa Hakko Kirin, Takeda, HUYA Bioscience International, Meiji Seika Kaisha, and Bristol Myers Squibb Japan; research funding from Eisai, HUYA Bioscience International, Daiichi Sankyo/UCB Japan, Bristol Myers Squibb Japan, Chugai Pharma, Byer, Kyowa Kirin International, and Regeneron Pharmaceutical; and has had an advisory or consulting role at HUYA Bioscience International, Yakult Pharmaceutical, Ono Pharmaceutical, Meiji Seika Kaisha, Solasia Pharma, and Daiichi Sankyo/UCB Japan. T.O. has received honoraria from Kyowa Hakko Kirin, Chugai Pharmaceutical Co Ltd, Novartis, Bristol Myers Squibb, Pfizer, Otsuka Pharmaceutical Co Ltd, Ono Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Astellas Pharma, Eisai Pharmaceuticals, Janssen Pharm, Daiichi Sankyo, Mundipharma, and Asahi Kasei Pharma; research funding from Celgene, Kyowa Hakko Kirin, Chugai Pharmaceutical Co, Ltd, TAIHO Pharmaceutical Co Ltd, and Asahi Kasei Pharma; and has participated in speaker’s bureaus at Novartis, Bristol Myers Squibb, Pfizer, and Otsuka Pharmaceutical Co Ltd. S.R. has participated in speaker’s bureaus at Chugai Pharmaceutical, Eisai Pharmaceutical, Ono Pharmaceuticals, and Janssen Pharmaceutical. K.K. has been employed by Bristol Myers Squibb, Daiichi Sankyo, and Shattuck Labs and owns stock in Bristol Myers Squibb and Celgene. K. Tobinai has received honoraria from Zenyaku Kogyo, Mundipharma, HUYA Bioscience International, Celgene, Daiichi Sankyo, and Solasia Pharma and has had an advisory or consulting role at Zenyaku Kogyo, HUYA Bioscience International, Daiichi Sankyo, and Mundipharma. K.Y. has received honoraria from AbbVie, Amgen, Celgene, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Kaken, Kyowa Kirin, Maruho, Meiji Seika Pharma, Minophagen, Novartis, Sanofi, Sun Pharma, Taiho, Torii, and UCB. K. Ishitsuka has received honoraria from Celgene, Kyowa Hakko Kirin, Bristol Myers Squibb Japan, Eisai, Pfizer, Daiichi Sankyo, Takeda, Chugai Pharma, CSL Behring, Nippon Shinyaku, Janssen, Sanofi, Ono Pharmaceutical, Astellas Pharma, Otsuka, and Meiji Seika Kaisha and research funding from Ono Pharmaceutical, Japan Blood Products Organization, Eisai, Taiho Pharmaceutical, MSD, Chugai Pharma, Dainippon Sumitomo Pharma, Asahi Kasei, Mochida Pharmaceutical Co Ltd, and Takeda. H.Y., M.T., Y.K., and N.A. are current employees of Daiichi Sankyo Co Ltd. The remaining authors declare no competing financial interests.

The current affiliation for K.K. is Shattuck Labs, Inc, Austin, TX.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Best percent change in tumor burden by disease compartment as assessed by IEAC. The best percent change in tumor burden is shown for nodal or extranodal lesions (A), skin lesions (B), and peripheral blood (C) in patients treated with valemetostat. The dashed line indicates a 50% reduction in tumor burden from baseline.

Figure 2.

Treatment duration with clinical outcomes and DOR. (A) The swimmer plot summarizes treatment duration of individual patients and best response. Patients ongoing in the study are denoted by arrows. (B) The Kaplan-Meier plot depicts the DOR. Tick marks denote censored patients. mDOR, median duration of response in months; NR, not reached.