Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study - 30/10/24

Doi : 10.1016/S1470-2045(24)00502-3

Dai Maruyama, MD ^a,^b,⁎ , Eric Jacobsen, MD ^c, Pierluigi Porcu, ProfMD ^d, Pamela Allen, MD ^e, Kenji Ishitsuka, ProfMD ^f, Shigeru Kusumoto, MD ^g, Tomoko Narita, MD ^g, Kensei Tobinai, MD ^a, Francine Foss, ProfMD ^h, Kunihiro Tsukasaki, ProfMD ⁱ, Tatyana Feldman, MD ^j, Yoshitaka Imaizumi, MD ^k,^l, Koji Izutsu, MD ^a, Satoko Morishima, MD ^m, Nobuhiko Yamauchi, MD ⁿ, Junichiro Yuda, MD ⁿ, Jonathan E Brammer, MD ^o, Toyotaka Kawamata, MD ^p,^q, Jia Ruan, ProfMD ^r, Kisato Nosaka, MD ^s, Atae Utsunomiya, MD ^t, Jie Wang, MD ^u, Jasmine Zain, ProfMD ^v, Yasuyuki Kakurai, PhD ^w, Hideyuki Yamauchi, MSc ^w, Yoshiyuki Hizukuri, PhD ^x, Noha Biserna, MSc ^x, Masaya Tachibana, PhD ^w, Ai Inoue, MD ^x, Steven M Horwitz, MD ^y

^a Department of Hematology, National Cancer Center Hospital, Tokyo, Japan

^b Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

^c Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

^d Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA

^e Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA

^f Department of Hematology and Rheumatology, Kagoshima University Hospital, Kagoshima, Japan

^g Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

^h Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA

ⁱ Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan

^j John Theurer Cancer Center at Hackensack Meridian Health School of Medicine, Hackensack, NJ, USA

^k Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan

^l Department of Hematology, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan

^m Graduate School of Medicine, University of the Ryukyus Hospital, Okinawa, Japan

ⁿ Department of Hematology, National Cancer Center Hospital East, Chiba, Japan

^o Division of Hematology, Department of Internal Medicine, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA

^p Department of Hematology/Oncology, The Institute of Medical Science, University of Tokyo, Tokyo, Japan

^q Department of Hematology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan

^r Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA

^s Department of Hematology, Rheumatology, and Infectious Diseases, Kumamoto University, Kumamoto, Japan

^t Department of Hematology, Imamura General Hospital, Kagoshima, Japan

^u Department of Medicine, Duke Cancer Institute, Durham, NC, USA

^v Department of Hematology and Hematopoietic Stem Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA

^w Daiichi Sankyo, Tokyo, Japan

^x Daiichi Sankyo, Basking Ridge, NJ, USA

^y Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

^* Correspondence to: Dr Dai Maruyama, Department of Hematology, National Cancer Center Hospital, Tokyo, 104-0045, Japan Department of Hematology National Cancer Center Hospital Tokyo 104-0045 Japan

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Summary

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.