Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study.

Background: Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas.
Methods: This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting.
Findings: Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4-17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3-4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6-65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150-250 mg per day.
Interpretation: The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting.
Funding: Daiichi Sankyo.
Competing Interests: Declaration of interests DM reports research funding from Ono, Janssen, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku, Sanofi, SymBio Pharmaceuticals, Takeda, AbbVie, AstraZeneca, Bristol Myers Squibb (BMS), Genmab, Novartis, Otsuka, Taiho, Pfizer, and Astellas; honoraria from Ono, Nippon Shinyaku, Janssen, Mundipharma, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku, Sanofi, SymBio Pharmaceuticals, Takeda, AbbVie, AstraZeneca, BMS, Genmab, and Novartis; and advisory board participation for Janssen, AstraZeneca, Chugai, AbbVie, Genmab, Sanofi, BMS, and Pfizer. EJ reports research funding from Celgene, Merck, Pharmacyclics, and F Hoffman-La Roche, unrelated to this work; honoraria from Merck, Daiichi, BMS, and Bayer, unrelated to this work; and planned patents, issued or pending with UpToDate, unrelated to this work. PP reports research funding from Ono; consulting fees from Dren Bio, Lilly-LOXO, Ono, Kiowa, and Daiichi Sankyo; honoraria from Viracta, Innate Pharma, Daiichi Sankyo, Kiowa, and Dren Bio; travel support from Dren Bio; participation in data and safety monitoring boards or advisory boards for Viracta, Innate Pharma, BeiGene, Kiowa, ADCT, Ono, and Lilly-LOXO. PA reports support from Daiichi Sankyo for the current work, and participation on an advisory board for Daiichi Sankyo. KIs reports manuscript support from Daiichi Sankyo, related to this work; research funding from Ono and Kyowa Kirin to their institutions, unrelated to this work; honoraria from Kyowa Kirin, Takeda, Chugai Pharmaceutical, Celgene, BMS, Daiichi Sankyo, Ono, Astellas, Eisai, Pfizer, Otsuka, Sanofi, CSL Behring, AbbVie, Yakult, Janssen, and Nippon Shinyaku, unrelated to this work; participation on data safety monitoring boards or advisory boards for Meiji Seika Pharma and Daiichi Sankyo, unrelated to this work; and items of value from Ono to their institution, unrelated to this work. SK has received support from Daiichi Sankyo, related to this work; research funding from Chugai, Kyowa Kirin, and Janssen, unrelated to this work; and honoraria from Daiichi Sankyo, Chugai, Kyowa Kirin, and Janssen, unrelated to this work. TN reports support from Daiichi Sankyo for the current work and institutional research support from Daiichi Sankyo. KTo reports consulting fees and honoraria from HUYA Bioscience, Daiichi Sankyo, and SymBio Pharmaceuticals. FF reports honoraria from Seagen, Acrotech, and Kyowa; participation on data safety monitoring boards and advisory boards for ASTX; and leadership or fiduciary roles on the US Cutaneous Lymphoma Consortium executive committee. KTs reports institutional support from Daiichi Sankyo for the current work; grants or contracts given to their institution from Kyowa Kirin, Meiji Seika Pharma, BMS, Bayer, Daiichi Sankyo, and HUYABIO; consulting fees from Meiji Seika Pharma, Daiichi Sankyo, HUYABIO, Ono, Solasia Pharma, and Yakuruto; honoraria from Chugai Pharma, Eisai, Takeda, Meiji Seika Pharma, and Sekisui Medical. TF reports research funding from ADCT, AstraZeneca, BMS, Corvus, Daiichi Sankyo, Genmab, Kymera, Merck, Seagen, Tessa, Trillium, Alexion, and Portola; consulting fees from ADCT, AstraZeneca, BMS, Epizyme, Genmab, Seagen, Phamacyclics, and Celgene; honoraria from Takeda, Seagen, Genmab, Epizyme, ADCT, AstraZeneca, BMS, Pharmacyclics, AbbVie, and Pfizer; and stock in OMI and Genomic Testing Cooperative. YI reports support for travel from Chugai, Meiji Seika Pharma, Sanofi, AstraZeneca, Daiichi Sankyo, BMS, SymBio Pharmaceuticals, and Kyowa Kirin. KIz has received manuscript support from Daiichi Sankyo to their institution, related to this work; research funding from Chugai, BMS, Incyte, Genmab, LOXO Oncology, Daiichi Sankyo, Beigene, AbbVie, AstraZeneca, Regeneron, Yakult, Chugai, Otsuka, Novartis, Pfizer, MSD, Bayer, Kyowa Kirin, Eisai, Janssen, Ono, Gilead, Astellas, and Amgen to their institution, unrelated to this work; consulting fees from AstraZeneca, Ono, Mitsubishi Tanabe, Eisai, Chugai, BMS, AbbVie, Takeda, Zenyaku, Genmab, Kyowa Kirin, MSD, Carna Biosciences, Novartis, Yakult, Nihon Shinyaku, Novartis, and Beigene, unrelated to this work; and honoraria from AstraZeneca, Ono, Eisai, Chugai, Janssen, SymBio Pharmaceuticals, BMS, Daiichi Sankyo, Otsuka, AbbVie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, Meiji Seika Pharma, Novartis, Nihon Kayaku, and Gilead, unrelated to this work. JR reports clinical trial support from Daiichi Sankyo, related to the current work. KN reports honoraria from Meiji Seika, Chugai, BMS, Kyowa Kirin, AbbVie, Daiichi Sankyo, Eisai, and Ohara. AU reports consulting fees from JIMRO and Otsuka Medical Devices, and honoraria from Meiji Seika Pharma, Kyowa Kirin, and BMS. JZ reports grand or contracts from Secura Bio, Astex, CRISPR, Myeloid, and Daiichi Sankyo; consulting fees from Seattle Genetics, Secura Bio, Kiyowa Kirin, and Myeloid; and honoraria from Kiowa Kirin. YK, HY, NB, and AI report employment with Daiichi Sankyo. MT and YH report employment with Daiichi Sankyo and stock options with Daiichi Sankyo. SMH received research funding from US National Cancer Institute Cancer Center Support Grant (P30 CA008748); research funding from ADC Therapeutics, Affimed, Aileron, Celgene, Crispr Therapeutics, Daiichi Sankyo, Forty Seven, Kyowa Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio; and honoraria from Abcuro, Autolus, Auxilius Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, DrenBio, Kyowa Kirin, March, Bio, Ono, SecuraBio, Shoreline, Biosciences, Takeda, Tubulis, and Yingli Pharma. All other authors declare no competing interests.
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