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653 Efficacy and Safety of Pevonedistat Plus Azacitidine Vs Azacitidine Alone in Higher-Risk Myelodysplastic Syndromes (MDS) from Study P-2001 (NCT02610777)

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Treatment of Higher Risk Myelodysplastic syndromes
Hematology Disease Topics & Pathways:
Follicular Lymphoma, ALL, multiple myeloma, Biological, Marginal Zone Lymphoma, Diseases, smoldering myeloma, CLL, Mantle Cell Lymphoma, LGLL, Therapies, CNS Lymphoma, MDS, DLBCL, enzyme inhibitors, Technology and Procedures, cytogenetics, Myeloid Malignancies
Monday, December 7, 2020: 11:30 AM

Mikkael A. Sekeres1, Justin M. Watts, MD2, Atanas Radinoff3*, Montserrat Arnan Sangerman, MD, PhD4*, Marco Cerrano5*, Patricia Font Lopez6*, Joshua F. Zeidner, MD7, Maria Diez-Campelo, PhD, MD8*, Carlos Graux9*, Jane L. Liesveld, MD10, Dominik Selleslag, MD11, Nikolay Tzvetkov, MD12*, Robert J. Fram13*, Dan Zhao13*, Sharon Friedlander13*, Kevin Galinsky13*, Douglas V. Faller13* and Ades Lionel14*

1Leukemia Program, Cleveland Clinic, Cleveland, OH
2University of Miami Sylvester Comprehensive Cancer Center, Miami, FL
3University Hospital Sveti Ivan Rislki, Sofia, Bulgaria
4Institut Català d'Oncologia-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet, Barcelona, Spain
5Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Turin, Turin, Italy
6Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
7University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC
8University Hospital of Salamanca, IBSAL Institute for Biomedical Research of Salamanca, Salamanca, Spain
9Université Catholique de Louvain, Centre Hospitalier Universitaire, Namur, Yvoir, Belgium
10The James P Wilmot Cancer Institute, University of Rochester, Rochester, NY
11AZ Sint Jan Brugge-Oostende, Brugge, Belgium
12MHAT Dr. Georgi Stranski, Clinic of Haematology, Pleven, Bulgaria
13Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA
14Hôpital Saint-Louis Hématologie Clinique, Paris, France

Background: Pevonedistat (P), the first small-molecule inhibitor of the neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme, disrupts proteasomal degradation of select proteins and has shown promising clinical activity and good tolerability in combination with azacitidine (A) in acute myeloid leukemia (AML).

Methods: 120 pts with higher-risk MDS/chronic myelomonocytic leukemia (Revised International Prognostic Scoring System [IPSS-R] risk >3, including intermediate- [≥5% blasts], high-, or very high-risk) or low-blast AML naïve to hypomethylating agents were randomized 1:1 to receive P 20 mg/m2 intravenously (IV) on days (d) 1, 3, 5 + A 75 mg/m2 (IV/subcutaneously) on d 1–5, 8, 9 (n=58), or A alone (n=62), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The study was powered for event-free survival (EFS – time from randomization to death/transformation to AML, whichever occurred first). These analyses focus on clinical, cytogenetic, and genetic factors that could impact rate, depth, and duration of response, as well as EFS and overall survival (OS), in pts with higher-risk MDS.

Results: The 67 pts with higher-risk MDS were drawn from a larger intent-to-treat (ITT) population (n=120), in which EFS trended longer (median 21.0 vs 16.6 months [mos]; hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.42–1.05; P = .076), and median OS was 21.8 vs 19.0 mos (HR 0.80; 95% CI 0.51–1.26; P =.334; median follow-up 21.4 vs 19.0 mos) with P+A vs A. In the higher-risk MDS pts, baseline characteristics were balanced between arms. Pts with higher-risk MDS received a median of 13.5 vs 10 cycles of P+A vs A, and EFS was longer with P+A vs A (median 20.2 vs 14.8 mos; HR 0.54; 95% CI 0.29–1.00; P = .045). Median OS was 23.9 vs 19.1 mos (HR 0.70; 95% CI 0.39–1.27; P = .240) with P+A vs A. Pts with MDS assessed as high-risk according to the combined Cleveland Clinic model formula [Nazha et al. Leukemia 2016;30:2214–20], which incorporates both clinical and genetic factors (n=16 in each arm), had a median EFS of 20.2 vs 11.7 mos (HR 0.39; 95% CI 0.17–0.90; P = .023) and a median OS of 24.2 vs 14.2 mos (HR 0.45; 95% CI 0.19–1.05; P = .056) with P+A vs A (Figure 1). In prespecified subgroup analyses of EFS among pts with IPSS-R-defined high- and very high-risk MDS, HRs favored P+A vs A (HR 0.47; 95% CI 0.19–1.18 and HR 0.53; 95% CI 0.17–1.72, respectively), as did overall response rate (complete remission [CR] + partial remission [PR] + hematologic improvement) in response-evaluable pts (79% vs 57%, with a CR rate of 52% vs 27% [P = .050] for P+A vs A). Median duration of response (CR + PR) was 34.6 vs 13.1 mos with P+A vs A (P = .106). Among pts with higher-risk MDS who were red blood cell (RBC) or platelet transfusion-dependent at baseline (P+A, n=13; A, n=19), 69.2% vs 47.4% became transfusion-independent (P = .228), and the median transfusion rate/month was 0.7 vs 2. Median duration of RBC and platelet transfusion-independence was 23.3 vs 11.6 mos (P = .016) with P+A vs A. Median time to AML transformation (range) among pts with higher-risk MDS who transformed (P+A, n=5; A, n=9) was 12.2 (4.6–12.6) vs 5.9 (1.7–14.8) mos with P+A vs A. Median dose intensity of A was 98% in both arms. Overall, P+A had a comparable safety profile to A alone and did not increase myelosuppression. In higher-risk MDS, rates of adverse events (AEs), serious AEs (SAEs), and grade ≥3 AEs normalized by the mean number of cycles dosed of A were lower with P+A compared with A (Table 1). Clinical activity was observed with P+A in pts who had poor-risk cytogenetics and in pts with adverse-risk mutations, including TP53 (Figure 2).

Conclusions: In pts with higher-risk MDS, P+A led to longer EFS and a higher CR rate compared with A; the effect on EFS was particularly evident in pts with IPSS-R high- and very-high-risk disease. This finding was associated with longer duration of response, later transformation to AML, increased rate of transfusion-independence and lower transfusion rates with P+A vs A. AEs, SAEs, and grade ≥3 AEs per A cycle dosed appeared lower with P+A vs A. Clinical activity was observed in pts with a variety of adverse-risk mutations, and a prognostic risk model that incorporates both clinical and genetic risk factors revealed potential clinical benefit among pts with high-risk MDS. Further evaluation of P+A vs A is ongoing in a randomized phase 3 trial (NCT03268954).

Disclosures: Sekeres: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Watts: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding. Radinoff: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Research Funding; Bulgarian Minister of Health: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Bayer: Research Funding; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Cerrano: Janssen: Research Funding; Jazz: Consultancy. Font Lopez: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees. Zeidner: AbbVie: Honoraria, Other: Independent Review Committee; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; AsystBio Laboratories: Consultancy; AROG: Research Funding; Merck: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Agios: Honoraria. Diez-Campelo: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Graux: Celgene/BMS: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Liesveld: Onconova: Other: data safety monitoring board. Selleslag: Teva: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Belgian College: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Fram: BeyondSpring Pharmaceuticals Inc.: Consultancy; Teva: Current equity holder in publicly-traded company; Baxter: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Vertex Phamaceuticals: Patents & Royalties: Patent 10/728,114; Gilead: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Takeda Pharmaceuticals Intl. Co.: Consultancy, Current Employment. Zhao: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Friedlander: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Galinsky: Takeda Pharmaceutical Company, Ltd: Current Employment. Faller: Briacell Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracta Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Phoenicia Biosciences: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Lionel: Jazz: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Celgene/BMS: Consultancy, Research Funding; Abbvie: Consultancy.

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

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