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2344 Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
AML, Diseases, Myeloid Malignancies
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Gail J. Roboz, MD1, Guillermo Sanz, MD, PhD2, Elizabeth A. Griffiths, MD3, Karen Yee, MD4, Hagop Kantarjian, MD5, Christian Recher, MD6, Michael T. Byrne, DO7, Elzbieta Patkowska, MD, PhD8*, Hee-Je Kim, M.D., Ph.D.9, Xavier Thomas, MD, PhD10, Ine Moors, MD11*, Wendy Stock, MD12, Arpad Illes, MD, PhD13*, Pierre Fenaux, MD, PhD14, Yasushi Miyazaki, MD, PhD15, Takahiro Yamauchi16, Casey L. O'Connell, MD17, Yong Hao, MD, PhD18*, Harold N. Keer, MD, PhD18, Mohammad Azab, MD18 and Hartmut Dohner, MD19

1Weill Cornell Medicine, The New York Presbyterian Hospital, New York, NY
2Hospital Universitari i Politècnic La Fe, Valencia and CIBERONC, IS Carlos III, Madarid, Spain
3Roswell Park Comprehensive Cancer Center, New York, NY
4Princess Margaret Cancer Centre, Toronto, ON, Canada
5Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX
6Institut Universitaire du Cancer Toulouse – Oncopole, Cedex, France
7Vanderbilt University Medical Center, Nashville, TN
8Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
9Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of (South)
10Hematology Department, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre-Benite, France
11Ghent University Hospital, Gent, Belgium
12University of Chicago Medical Center, Chicago, IL
13University of Debrecen, Debrecen, Hungary
14Hôpital Saint-Louis, Paris, France
15Nagasaki University Hospital, Fukui, Japan
16University of Fukui Hospital, Yoshida-gun, Fukui, Japan
17USC Keck School of Medicine, University of Southern California, Los Angeles, CA
18Astex Pharmaceuticals, Inc., Pleasanton, CA
19University Hospital of Ulm, Ulm, Germany

Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study (ASTRAL-2) of G vs TC in AML patients who were either refractory to or relapsed (r/r) after prior anthracycline-based intensive chemotherapy with or without hematopoietic cell transplant (HCT).

Methods: r/r AML patients were randomized to G (60 mg/m2 SC/d for 10 days in first 1-2 cycles followed by 5-day cycles Q 28 days) vs Treatment Choice (TC). TC were preselected prior to randomization to either low intensity (LI) treatment; high intensity (HI) chemotherapy; or Best Supportive Care (BSC). LI choices were other HMAs of azacitidine or decitabine, or low-dose Ara-C (LDAC) at their standard doses. HI choices were high-dose Ara-C (HiDAC), MEC, or FLAG± Ida combination chemotherapy at standard doses. Primary endpoint was overall survival (OS) based on ITT analysis with secondary endpoints including 12 and 24-month survival rates, complete response (CR), event-free survival (EFS), and safety. P values for secondary endpoints and subgroups are nominal as there was no adjustment of p values for multiple analyses.

Results: 302 patients were randomized to G (148) or TC (154). Preselected TCs were mainly LI (77%) predominantly HMAs (86% of the patients randomized to LI), or HI (21%), with only 6 patients (2%) in the BSC subset. Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥65 y in 51.4% vs 40.3% with median age 65y vs 63y, ECOG PS 2 in 15.5% vs 20.8%, poor risk cytogenetics in 44.6% vs 42.2%, refractory AML in 44.6% vs 33.1%, prior HCT in 18.2% vs 26%, a majority of patients were in second or subsequent relapse after ≥ 2 prior therapies (54.7% vs 56.5%).

Median number of treatment cycles was short (3 cycles for G vs 2 cycles for TC). Median follow up was 21.6 months. Most common causes of treatment discontinuation were disease progression (35.2% for G vs 38.1% for TC), or death (15.2% for G vs 18.4% for TC).

Median OS on G was 6.4 months vs 5.4 months for TC and not statistically significant (OS HR 0.88, 95% CI 0.67, 1.14, log rank p value 0.3). There was no significant difference in OS between G and each of the LI and HI preselected subsets. However, several other planned prospective subgroups favored G with OS HR 95% CI upper limit ≤ 1.0 including patients <65y (HR 95% CI 0.47, 0.97, p 0.032) ; ECOG PS 0-1 (HR 95% CI 0.57, 1.0, p 0.049); refractory AML (HR 95% CI 0.38, 0.89, p 0.013); lower peripheral blood (PB) disease burden of ≤ 30% PB blasts (HR 95% CI 0.46, 0.92, p 0.015); and those who received at least 4 cycles in either treatment arm (HR 95% CI 0.36, 0.95, p 0.031). The 12- and 24-month survival rates for G vs TC respectively were 32% vs 26%; and 19% vs 10%. Median EFS was short with 3 months for G vs 2.4 months for TC; log rank p 0.005. CR rate was 12.8% for G vs 7.1% for TC (p 0.051). CR + CR with partial hematologic recovery (CRh) rate was double for G with 16.9% compared to 7.8% for TC (p 0.007). Composite CR (CRc) or CR+ CR with incomplete hematologic recovery (CRi) rate was 27% for G vs 14.3% for TC (p 0.003).

Adverse events (AEs) of grade ≥3, regardless of relationship to treatment, were 89% on G vs 84% on TC. Most common Grade ≥3 AEs for G vs TC respectively were febrile neutropenia (38.6% vs 38.1%); neutropenia (32.4% vs 17%); thrombocytopenia (28.3% vs 29.9%); anemia (21.4% vs 24.5%); pneumonia (18.6% vs 20.4%); and sepsis (11.7 vs 10.9%). None of the differences were significant except for neutropenia (p 0.003).

Summary/Conclusions: In this randomized study in r/r AML after intensive chemotherapy, G did not significantly improve OS compared to standard of care TC composed mainly of LI treatment with other HMAs. The data suggest that G may be better than TC in in some of the secondary endpoints (24-month survival rate, EFS, CR, CR+CRh, and CRc). Prospective subgroup analyses of OS suggest that younger (<65 y), more fit patients (PS 0-1); with lower PB disease burden (PB blasts ≤ 30%), and those who could receive at least 4 cycles may benefit from G. The results of secondary endpoints and subgroup analyses should be interpreted with caution. Grade ≥3 AEs were the expected hematological and infection AEs with no significant differences between G and TC except for significantly higher incidence of neutropenia with G.

Disclosures: Roboz: Actinium: Consultancy; Mesoblast: Consultancy; Janssen: Research Funding; AbbVie: Consultancy; Astex: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Agios: Consultancy; Glaxo SmithKline: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Helsinn: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Sanz: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding, Speakers Bureau. Griffiths: Astex Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Genentech: Research Funding. Yee: Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TaiHo: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Geron: Research Funding; Janssen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Kantarjian: Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Jazz: Research Funding; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Recher: Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: 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. Byrne: Karyopharm: Research Funding. Patkowska: Astellas Pharma, Inc.: Consultancy, Other: Travel fees; KCR US, Inc.: Consultancy; Bristol-Myers Squibb: Other: Travel fees; Jazz Pharmaceuticals: Other: Travel fees; Angelini Pharma: Honoraria, Other: Travel fees; Novartis: Honoraria, Other: Travel fees; Servier: Honoraria, Other: Travel fees; Pfizer: Other: Travel fees; AMGEN: Honoraria. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Illes: Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses. Fenaux: Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Miyazaki: Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Daiichi-Sankyo: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Kyowa-Kirin: Honoraria; Chugai: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Sanofi: Honoraria. Yamauchi: Daiichi Sankyo: Research Funding; Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Solasia Pharma: Research Funding. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Dohner: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria; Agios: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; GEMoaB: Honoraria; Gilead: Honoraria; Helsinn: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria.

*signifies non-member of ASH