Fully Oral Combination of Decitabine/Cedazuridine (ASTX727) Plus Venetoclax for the Treatment of Newly Diagnosed Acute Myeloid Leukemia in Patients Ineligible for Intensive Chemotherapy

Introduction: Decitabine/cedazuridine (ASTX727) is an oral formulation of decitabine with equivalent AUC exposure compared to IV decitabine. The combination of ASTX727 plus venetoclax offers fully oral therapy for acute myeloid leukemia (AML) in patients ineligible for standard intensive chemotherapy-based approaches due to age or comorbidities. We present here updated results of a phase 2 study evaluating ASTX727 plus venetoclax for patients with newly diagnosed AML.

Methods: This was a single center phase 2 study that enrolled patients with newly diagnosed AML ≥ 18 years and ineligible for intensive chemotherapy, defined as at least one of the following: age ≥ 75 years, ECOG performance status of 2-3, clinical congestive heart failure, LVEF ≤ 50%, DLCO ≤ 65%, or FEV1 ≤ 65%. Patients with acute promyelocytic leukemia (APL) and those with central nervous system leukemia were excluded. This study also included a relapsed/refractory cohort which is not presented here. The treatment regimen consisted of ASTX727 35/100 mg on days 1-5 plus venetoclax 400 mg (azole adjusted) on days 1-28, every 28 days. Venetoclax was stopped on day 21 if bone marrow examination showed blasts < 5%. Dose reductions of both ASTX727 and venetoclax were permitted in consolidation cycles (cycles 2 and onwards). Treatment continued until progression or limiting toxicity for up to 24 cycles. The primary objective was overall response rate (ORR). Secondary objectives were overall survival (OS), relapse-free survival (RFS), and safety/tolerability. This study is registered on ClinicalTrials.gov (NCT04746235).

Results: 60 patients have been enrolled in the frontline cohort. The median age was 80 years (range 50-92) and 21/60 (35%) were female. By ELN 2022 risk, 8 (13%) patients were favorable, 4 (7%) were intermediate, and 48 (80%) were adverse. 15 (25%) patients had complex cytogenetics, 9 (15%) had TP53 mutations, 9 (15%) had therapy-related AML, and 25 (42%) had AML arising from antecedent MDS/MPN, including 11 (18%) with prior hypomethylating agent (HMA) exposure for MDS.

The median number of cycles given was 3 (range 1-21). The median follow-up time was 20 months. The ORR was 40/60 (67%), including 24 (40%) complete remission (CR), 13 (22%) CR with incomplete count recovery (CRi), and 3 (5%) morphologic leukemia-free state (MLFS). Of 37 responding patients with adequate samples, measurable residual disease (MRD) was negative in 19/37 (51%). The median OS was 10.2 months for the full frontline cohort and the median RFS in patients achieving CR/CRi (n=37) was 9.8 months. When excluding patients with prior HMA exposure (n=11), the median OS was 12.7 months and the median RFS was 9.9 months. We next stratified patients into 3 categories of benefit as described by Döhner and colleagues (ASH 2022). Patient with high predicted benefit were those without TP53, FLT3-ITD or N/KRAS mutations. Patients with FLT3-ITD or N/KRAS were intermediate benefit, and those with TP53 mutations were low benefit. The median OS was 16.2, 9.1, and 2.2 months in patients with high (n=34), intermediate (n=17), or low (n=9) predicted benefit, respectively (p<0.01). The median RFS was 12.6, 6.1, and 8.6 months in patients with high (n=23), intermediate (n=11), or low (n=3) predicted benefit, respectively (p=0.03). Only 3 (5%) patients went off study to receive stem cell transplantation. The most common grade 3/4 treatment-emergent adverse events were neutropenic fever (10%), pneumonia (8%), neutropenia (8%), bacteremia (7%), thrombocytopenia (7%), and respiratory failure (7%). Grade 3/4 infections of any type occurred in 27% of patients. 3 deaths occurred on study treatment in patients in remission and were potentially treatment-related (1 from bleeding and 2 from infections).

Conclusions: ASTX727 plus venetoclax allows for effective fully oral therapy in chemotherapy-ineligible older patients with newly diagnosed AML. OS is comparable to that obtained with parenteral azacitidine plus venetoclax (VIALE-A) in HMA-naïve patients. No new clinically relevant safety signals were observed.

Garcia-Manero:Onconova: Research Funding; Astex: Research Funding; Amphivena: Research Funding; Helsinn: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Curis: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; Helsinn: Other: Personal fees; Genentech: Other: Personal fees. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Montalban-Bravo:Rigel: Research Funding; Takeda: Research Funding. Pemmaraju:Neopharm: Honoraria; ClearView Healthcare Partners: Consultancy; LFB Biotechnologies: Honoraria; Springer Science + Business Media: Honoraria; Bristol-Myers Squibb: Consultancy; Aptitude Health: Honoraria; Celgene: Honoraria, Other: Travel Expenses; Roche Molecular Diagnostics: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Incyte: Honoraria; Protagonist Therapeutics: Consultancy; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Pacylex: Consultancy; CareDx: Honoraria; Blueprint Medicines: Consultancy, Honoraria; CTI BioPharma: Consultancy; Immunogen: Consultancy; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Triptych Health Partners: Consultancy; Affymetrix/Thermo Fisher Scientific: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Issa:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Celgene: Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Merck: Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding. Short:Sanofi: Honoraria; NextCure: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Novartis: Honoraria; Autolus: Honoraria; Stemline Therapeutics: Research Funding; Xencor: Research Funding; Amgen: Honoraria; BeiGene: Honoraria; Pfizer Inc.: Honoraria; Adaptive Biotechnologies: Honoraria; GSK: Consultancy, Research Funding; Takeda Oncology: Honoraria, Research Funding. Kadia:JAZZ: Research Funding; Novartis: Honoraria; Sellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Cellenkos: Research Funding; Rigel: Honoraria; Regeneron: Research Funding; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; Incyte: Research Funding; ASTEX: Research Funding; Amgen: Research Funding; Abbvie: Consultancy, Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Pfizer: Research Funding; Servier: Consultancy. Jain:AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Dialectic Therapeutics: Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Medisix: Research Funding; Aprea Therapeutics: Research Funding; NovalGen: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; TransThera Sciences: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; MingSight: Honoraria, Research Funding; Servier: Research Funding; Fate Therapeutics: Research Funding; Newave: Research Funding; Pfizer: Research Funding; Loxo Oncology: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Masarova:Cogent: Other: Advisory Board Participant; GSK: Consultancy, Other: Travel support; PharmaEssentia: Other: Advisory Board Participant; MorphoSys: Other: Advisory Board Participant. Daver:Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Trovagene: Research Funding; Jazz: Consultancy; Syndax: Consultancy; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Menarini Group: Consultancy; Agios: Consultancy; KITE: Research Funding; Arog: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Hanmi: Research Funding; Shattuck Labs: Consultancy; Trillium: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Maiti:Inspirna: Research Funding; Indapta Therapeutics: Research Funding; CytoMed Therapeutics: Research Funding; Hibercell Inc.: Research Funding; Chimeric Therapeutics: Research Funding; Lin Biosciences: Research Funding. Chien:AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Abbas:Blueprint Medicines Corporation: Research Funding; Enzyme By Design: Research Funding; GlaxoSmithKline: Research Funding; Ascentage: Research Funding; Molecular Partners: Consultancy; Genentech: Research Funding; Illumina: Honoraria, Other: Inkind Support, Research Funding; Alamar Biosciences: Honoraria. Ohanian:Bio-Path Holdings, Inc.: Consultancy. DiNardo:Rigel: Research Funding; Jazz: Consultancy, Honoraria; Notable Labs: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Immunogen: Honoraria; Schrodinger: Consultancy, Honoraria; Foghorn: Research Funding; Gilead: Consultancy; Cleave: Research Funding; ImmuneOnc: Research Funding; Riegel: Honoraria; Loxo: Research Funding; Astellas: Consultancy, Honoraria; Astex: Research Funding; Amgen: Consultancy; GSK: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Ravandi:BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Xencor: Research Funding; Abbvie: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding.

ASTX727 is not currently approved for AML by the FDA