-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1731 Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphomas, B Cell lymphoma, Clinical Research, Diseases, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Koji Izutsu, MD, PhD1, Kenji Ishitsuka, MD, PhD2*, Dai Maruyama, MD, PhD1, Kunihiro Tsukasaki, MD, PhD3, Shigeru Kusumoto, MD, PhD4, Yasuyuki Kakurai, PhD5*, Hideyuki Yamauchi, MSc5*, Ai Inoue, MD, PhD6*, Masaya Tachibana, PhD5*, Shinji Tsutsumi, PhD6* and Kensei Tobinai, MD, PhD1

1National Cancer Center Hospital, Tokyo, Japan
2Department of Hematology and Rheumatology, Kagoshima University Hospital, Kagoshima, Japan
3Department of Hematology, Saitama Medical University International Medical Center, Saitama, Japan
4Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
5Daiichi Sankyo Co., Ltd., Tokyo, Japan
6Daiichi Sankyo Inc., Basking Ridge, NJ

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development.

Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL.

Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan & US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150–300 mg/day (d) in continuous 28-d treatment (Tx) cycles.

Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan–Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts.

Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44–88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0–6); no pt in this cohort had received prior hematopoietic cell transplantation.

Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts.

The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4–71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR (Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx (Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9–10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (Cmax) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to Cmax (Tmax) of 3.9 (range 0.2–27.8) h and a mean [SD] AUCtau of 17,500 [21,400] ng × h/mL.

Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150–300 mg/d. Clinical responses were durable, with a median DOR of > 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R2) in the US (NCT05683171).

Disclosures: Izutsu: MSD: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy; Mitsubishi Tanabe Pharma: Consultancy; Nippon Shinyaku: Consultancy; Astellas Amgen: Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Yakult: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Beigene: Research Funding; Loxo Oncology: Research Funding; Regeneron: Research Funding; Janssen: Honoraria; SymBio Pharmaceuticals: Honoraria; Eli Lilly: Honoraria; Meiji Seika: Honoraria; Nihon Kayaku: Honoraria; Pfizer: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Ono Pharmaceuticals: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Otsuka: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Ishitsuka: Genmab: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Ono Pharmaceutical: Honoraria; Novartis: Honoraria; Nippon Shinyaku: Honoraria; Nippon Kayaku: Honoraria; Janssen: Honoraria; Eizai: Honoraria; CSLbehring: Honoraria; Chugai Pharmaceutical: Honoraria; Bristol Myers Squibb: Honoraria; Abbvie: Honoraria; Ono Pharmaceutical: Research Funding; Yakult: Consultancy; Meiji Seika: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Takeda: Honoraria. Maruyama: MSD: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Otsuka: Research Funding; Janssen: Honoraria, Research Funding; Ono: Honoraria, Research Funding; AstraZeneca: Honoraria; SymBio: Honoraria; Novartis: Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Research Funding; Eisai: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Astellas: Research Funding; Amgen Astellas Biopharma: Research Funding; Nippon Shinyaku: Honoraria; Mundipharma: Honoraria; Zenyaku: Honoraria. Tsukasaki: Daiich-Sankyo: Consultancy, Research Funding; HUYABIO: Consultancy, Research Funding; Ono Pharma: Consultancy; Solasia Pharma: Consultancy; Yakuruto: Consultancy; Kyowa-hakko/Kirin: Research Funding; Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Regeneron Pharmaceuticals Inc.: Research Funding; Chugai Pharma: Honoraria; Eizai: Honoraria; Takeda: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding. Kusumoto: Daiichi-Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Shionogi: Research Funding; Ono: Honoraria; Eil Lilly: Honoraria; Takeda: Honoraria; Kyowa-Kirin: Honoraria; Astellas: Honoraria; Eisai: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Nippon-Shinyaku: Honoraria; SymBio: Honoraria; Meiji-Seika: Honoraria; Mundipharma: Honoraria. Kakurai: Daiichi Sankyo Co., Ltd.: Current Employment. Yamauchi: Daiichi Sankyo Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Inoue: Daiichi Sankyo Inc.: Current Employment. Tachibana: Daiichi Sankyo Co., LTD.: Current Employment. Tsutsumi: Daiichi Sankyo Inc.: Current Employment. Tobinai: HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Solasia Pharma: Honoraria; Celgene: Honoraria; Mundipharma: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria.

*signifies non-member of ASH