Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin lymphoma (NHL), with limited available treatment options for patients (pts) with relapsed or refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for pts with R/R PTCL treated with valemetostat in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (DS3201-A-U202; NCT04703192).
Methods: Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Pts received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review of PTCL following computed tomography (CT)-based response assessment according to Lugano 2014 criteria. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Positron emission tomography (PET)-CT-based response assessment by Lugano 2014 criteria was an exploratory endpoint. Efficacy analyses included all pts who received ≥ 1 dose of valemetostat and had an eligible PTCL subtype confirmed by central hematopathology review; safety analyses included all pts who received ≥ 1 dose of valemetostat.
Results: A total of 133 pts with R/R PTCL were enrolled and received ≥ 1 dose of valemetostat. Pts had a median age of 69 years (range 22-85) and 91 pts (68.4%) were male. Pts had received a median of 2 prior lines of therapy (range 1-12) and 35 pts (26.3%) received prior hematopoietic cell transplant (HCT; autologous, n = 32; allogeneic, n = 5). PTCL subtype eligibility was confirmed in 119 pts: 42 pts (31.6%) had angioimmunoblastic T-cell lymphoma (AITL), 41 (30.8%) had PTCL, not otherwise specified (PTCL, NOS), 9 (6.8%) had ALCL (7 [5.3%] ALK-negative and 2 [1.5%] ALK-positive), 8 (6.0%) had nodal PTCL with T follicular helper cell phenotype, and 19 (14.3%) had other PTCL subtypes.
As of data cutoff (May 5, 2023), 32 pts (24.1%) were still receiving treatment; reasons for treatment discontinuation included progressive or relapsed disease in 46 pts (34.6%), clinical progression in 19 pts (14.3%), adverse event in 13 pts (9.8%), and 12 pts (9.0%) discontinued study drug to proceed with allogeneic HCT. Median treatment duration was 18 weeks (range 0.3-93.4) and median duration of follow-up was 10.5 months (range 0.2-21.5).
Among 119 efficacy-evaluable pts, the CT-based ORR was 43.7% (n = 52) (95% confidence interval [CI], 34.6-53.1), including 17 pts (14.3%) achieving CR and 35 pts (29.4%) achieving PR as best overall response. Median DOR was 11.9 months (95% CI, 7.8-not evaluable [NE]) and median time to response was 8.1 weeks (range 5-37). ORR by PTCL subtype ranged from 31.7% for PTCL, NOS to 54.8% for AITL (Table 1). Using PET-CT-based response assessment, ORR was 52.1% (n = 62) (95% CI, 42.8-61.3), including 32 pts (26.9%) with a complete metabolic response. Median CT-based PFS was 5.5 months (95% CI, 3.5-8.3) and median OS was 17.0 months (95% CI, 13.5-NE).
Of 133 pts in the safety analysis set, 128 pts (96.2%) experienced ≥ 1 treatment-emergent adverse event (TEAE) of any grade, 77 pts (57.9%) experienced grade ≥ 3 TEAEs, and 53 pts (39.8%) experienced serious adverse events. The most common all grade and grade ≥ 3 TEAE was thrombocytopenia (Table 2). Overall, 13 pts (9.8%) experienced a TEAE that led to treatment discontinuation, 21 pts (15.8%) had a TEAE that led to dose reduction, and 66 pts (49.6%) had a TEAE that led to dose interruption.
Conclusions: Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL.
Disclosures
Horwitz:ADC Therapeutics: Research Funding; Yingli Pharma Limited: Consultancy; Tubulis: Consultancy; Takeda: Consultancy, Research Funding; SecuraBio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Auxilius Pharma: Consultancy; Abcuro Inc.: Consultancy; Cimieo Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Research Funding; ONO Pharmaceuticals: Consultancy; Affimed: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Crispr Therapeutics: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Verastem/SecuraBio: Research Funding. Izutsu:Otsuka: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Ono Pharmaceuticals: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; MSD: Honoraria, Research Funding; Pfizer: 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; Eisai: Consultancy, Honoraria, Research Funding. Mehta-Shah:Innate Pharmaceuticals: Research Funding; Genentech/Roche: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Corvus Pharmaceuticals: Research Funding; C4 Therapeutics: Consultancy, Research Funding; Celgene: Research Funding; Bristol Myers-Squibb: Research Funding; AstraZeneca: Consultancy, Research Funding; Secura Bio/Verastem: Consultancy, Research Funding; Genentech: Consultancy; Kyowa Hakko: Consultancy; Janssen: Consultancy; Ono Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy. Cordoba:Fundacion Jimenez Diaz University Hospital: Current Employment; F. Hoffmann-La Roche Ltd, Takeda, Abbvie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, Genmab, Incyte, Gilead: Speakers Bureau; F. Hoffmann-La Roche Ltd, Takeda, Abbvie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, Genmab, Incyte, Gilead: Consultancy; European Hematology Association (EHA), Spanish Society Hematology (SEHH): Membership on an entity's Board of Directors or advisory committees. Barta:Janssen (Independent Data Monitoring Committee): Membership on an entity's Board of Directors or advisory committees; Acrotech: Consultancy; Affimed: Consultancy; Daiichi Sankyo: Consultancy; Kyowa Kirin: Consultancy. Bachy:Incyte: Honoraria; Novartis: Honoraria, Other: Personal Fees; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Hospices Civils de Lyon Claude Bernard Lyon 1 University: Current Employment; Pfizer: Honoraria, Other: Personal Fees; Amgen: Research Funding; Kite, a Gilead Company: Honoraria, Other: Personal Fees; Roche: Consultancy, Honoraria. Gritti:Roche, Sandoz, Beigene, Janssen: Other: Support for attending meetings; F. Hoffmann-La Roche Ltd, Takeda, Kite-Gilead, Ideogen, Genmab, Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Clinigen, Sandoz, Beigene, Incyte, Janssen, Novartis: Other; Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, Genmab: Other: Advisory Board; Takeda: Consultancy; Takeda, Clinigen, Ideogen, Beigene, Incyte, Novartis: Other: Training activity; Takeda: Consultancy. Jacobsen:BMS: Honoraria; Bayer: Honoraria; Pharmacyclics: Research Funding; Hoffman-LaRoche: Research Funding; Merck: Honoraria, Research Funding; Celgene: Research Funding; UpToDate: Patents & Royalties; Daiichi: Honoraria. Kusumoto:Shionogi: Research Funding; Nippon-Shinyaku: Honoraria; AbbVie: Honoraria; Bristol Myers Squibb: Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Ono: Honoraria; Eil Lilly: Honoraria; Eisai: Honoraria; Takeda: Honoraria; Astellas: Honoraria; SymBio: Honoraria; Kyowa-Kirin: Honoraria; Meiji-Seika: Honoraria; AstraZeneca: Honoraria; Mundipharma: Honoraria. Guillermin:Pfizer: Consultancy. Prica:Astra-Zeneca: Honoraria; Kite-Gilead: Honoraria. Yoon:Samyang: Research Funding; Pharos iBio: Consultancy; Beigene: Consultancy; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Kirin Pharm: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Boryung: Research Funding; Abclon: Consultancy; GI cell: Consultancy; GC cell: Consultancy. Domingo Domenech:BeiGene: Consultancy; BMS: Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Wang:Daiichi Sankyo: Research Funding; MacroGenics Inc: Research Funding; SecuraBio: Research Funding. Cwynarski:Abbvie: Membership on an entity's Board of Directors or advisory committees; : Roche, Takeda, Celgene, Atara, Gilead, KITE, Janssen, Incyte, Abbvie: Consultancy, Honoraria; Roche, Takeda, KITE, Gilead, Incyte: Speakers Bureau; Roche, Takeda, KITE, Janssen, BMS: Other: Conferences/Travel support. van der Poel:Incyte: Consultancy; Kite/Gilead: Honoraria; Takeda: Honoraria. Inoue:Daiichi Sankyo Inc.: Current Employment. Jin:Daiichi Sankyo Stocks: Current equity holder in publicly-traded company; Daiichi Sankyo Inc.: Current Employment. Wu:Daiichi Sankyo: Current Employment. Nakajima:Daiichi Sankyo: Current Employment, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Zinzani:JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SECURA BIO: Membership on an entity's Board of Directors or advisory committees; ASTRAZENECA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; INCYTE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC THERAPEUTICS: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; BEIGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
