Pevonedistat (PEV) + Azacitidine (AZA) Versus AZA Alone As First-Line Treatment for Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) with 20-30% Marrow Blasts: The Randomized Phase 3 PANTHER Trial (NCT03268954)
Authors: Sekeres Mikkael A. , Girshova Larisa , Doronin Vadim A , Diez-Campelo Maria , Valcarcel David , Kambhampati Suman , Viniou Nora-Athina , Woszczyk Dariusz , De Paz Arias Raquel , Symeonidis Argiris , Anagnostopoulos Achilles , Ciliao Munhoz Eduardo , Platzbecker Uwe , Santini Valeria , Fram Robert J. , Yuan Ying , Faller Douglas V. , Ades Lionel 
Published: November 2021

Abstract
Background:
Older patients with higher-risk MDS/CMML or AML with 20-30% marrow blasts typically receive single-agent hypomethylating agent (HMA) therapy. Median response duration and survival for these patients is poor, and many patients with MDS transform to secondary AML, which is associated with a particularly dismal prognosis. Novel HMA-based combination therapies that improve survival, delay transformation to AML, and increase depth and duration of response vs single-agent HMA therapy without additional toxicity or myelosuppression are needed. In a randomized, proof-of-concept phase 2 study PEV - a first-in-class, selective inhibitor of NEDD8-activating enzyme - in combination with AZA demonstrated encouraging clinical efficacy vs AZA alone in patients with higher-risk MDS and AML with 20-30% marrow blasts, with nearly double the complete remission rate, almost triple the duration of response, and improved event-free survival (EFS) among patients with higher-risk MDS (Sekeres Leukemia 2021). PEV + AZA had a comparable safety profile to AZA alone, without increased myelosuppression. Here we report the study design and patient characteristics from PANTHER, a global, multicenter, randomized phase 3 trial (NCT03268954).
Methods:
Patients aged ≥18 years with a confirmed diagnosis of higher-risk MDS or higher-risk CMML (Revised International Prognostic Scoring System [IPSS-R] risk score &gt;3; ≥5% marrow blasts for intermediate-risk patients) or AML with 20-30% marrow blasts and who were chemotherapy/HMA-naïve and ineligible for upfront intensive chemotherapy and/or allogeneic stem cell transplantation were randomized 1:1 to receive PEV 20 mg/m 2 (IV, days 1, 3, 5) + AZA 75 mg/m 2 (IV or subcutaneous; days 1-5, 8, 9) or AZA alone in 28-day cycles until unacceptable toxicity, relapse, progressive disease, or transformation to AML. Patients were stratified into 4 categories: very high, high, and intermediate risk (per IPSS-R) MDS/CMML, and AML with 20-30% marrow blasts. The primary endpoint was EFS, defined as time from randomization to death or transformation to AML for patients with higher-risk MDS or higher-risk CMML, or to death for patients with AML. OS was a key secondary endpoint. EFS and OS are being tested sequentially in the higher-risk MDS cohort and intent-to-treat (ITT) population using separate hierarchical testing procedures (total 1-sided alpha of 0.025 for each procedure), with subsequent OS testing in the AML cohort.
Results:
A total of 454 patients were randomized (PEV + AZA, n=227; AZA alone, n=227), 324 with higher-risk MDS (n=161; n=163), 103 with AML (n=50; n=53), and 27 with higher-risk CMML (n=16; n=11). Baseline demographics and disease characteristics were generally well balanced between arms. In the ITT population, 58% and 63% of patients in the PEV + AZA and AZA alone arms, respectively, were male, 91% and 86% were aged ≥65 years (41% and 48% aged ≥75 years), and 89%/10% and 84%/15% had an Eastern Cooperative Oncology Group performance status of 0 or 1/2. In patients with higher-risk MDS who were treated with PEV + AZA or AZA alone, IPSS-R risk group was very high in 39% and 36%, high in 37% and 39%, and intermediate in 24% and 25%; 93% and 94% of patients had de novo disease. In patients with AML treated with PEV + AZA or AZA alone, 60% and 70% were classified as adverse-risk per European LeukemiaNet 2017 guidelines; 62% and 49% had de novo disease. To date, no new safety signals have been identified. At the prespecified second interim analysis for the primary endpoint of EFS (n=147 events, higher-risk MDS), approximately 202 OS events had also occurred.
Conclusions:
Patient characteristics were well-balanced between arms, and the population is reflective of typical patients with higher-risk MDS/CMML and AML with 20-30% marrow blasts. EFS and OS in the ITT population and the higher-risk MDS cohort for each treatment arm will be presented, along with data on secondary endpoints, including response rates and duration of response, time to AML transformation in patients with higher-risk MDS, rates of transfusion independence, and safety. If endpoints are met, this would be the first phase 3 study in this setting to demonstrate superior efficacy with addition of a novel agent to AZA.

Disclosures
Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Girshova: Astellas Pharma, Inc.: Research Funding. Diez-Campelo: Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Valcarcel: ASTELLAS: Consultancy, Honoraria, Speakers Bureau; NOVARTIS: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; JAZZ: Consultancy, Honoraria, Speakers Bureau; SOBI: Consultancy, Honoraria, Speakers Bureau; SANOFI: Consultancy, Honoraria, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; CELGENE: Consultancy, Honoraria, Speakers Bureau. Viniou: Abbvie: Research Funding; Pfizer: Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Honoraria, Research Funding; Takeda: Research Funding; Sandoz: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Roche: Research Funding; Astellas: Research Funding; Celgene: Research Funding. De Paz Arias: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Symeonidis: Astellas: Consultancy, Research Funding; Demo: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials . Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria. Santini: Astex: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Fram: Takeda Pharmaceuticals Intl. Co: Current Employment; Takeda: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Baxter: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Teva: Current equity holder in publicly-traded company; Viatris: Current equity holder in publicly-traded company; Medtronics: Current equity holder in publicly-traded company; Zimmer Biomet Hldgs Inc: Current equity holder in publicly-traded company. Yuan: Takeda: Current Employment. Faller: Briacell, Inc: Current holder of stock options in a privately-held company; Takeda Pharmaceuticals Co.: Current Employment; Viracta Therapeutics, Inc: Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees. Ades: ABBVIE: Honoraria; NOVARTIS: Honoraria; CELGENE/BMS: Honoraria; TAKEDA: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding.

OffLabel Disclosure:
This presentation contains information about investigational use of pevonedistat. Safety and efficacy have not been determined.