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4277 Personalized Oral Maintenance Therapy with Decitabine/Cedazuridine (ASTX727) Combined with a Molecularly Targeted Agent (Venetoclax, Gilteritinib, Ivosidenib, or Enasidenib) in Acute Myeloid Leukemia in First Remission

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Alexandre Bazinet, MD1*, Naval Daver, MD2, Farhad Ravandi, MBBS3, Nicholas J. Short, MD1, Musa Yilmaz, MD1*, Maro Ohanian, DO1*, Jo Ishizawa, MD, PhD4, Abhishek Maiti, MBBS5, Courtney D. DiNardo, MD, MSc6, Lucia Masarova, MD1, William G. Wierda7, Kelly S. Chien, MD8, Elias Jabbour, MD7, Danielle Hammond, MD1, Fadi G. Haddad, MD1, Koji Sasaki, MD1, Alex Bataller, MD, PhD1*, Debra Bull-Linderman, RN9*, Gautam Borthakur, MD4, Guillermo Garcia-Manero, MD1, Hagop M. Kantarjian, MD10 and Tapan M. Kadia, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
4Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas Health Science Center At Houston, Houston, TX
6Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
7The University of Texas MD Anderson Cancer Center, Houston, TX
8Department of Leukemia, MD Anderson, Houston, TX
9Department of Leukemia, MD Anderson Cancer Center, Houston, TX
10University of Texas MD Anderson Cancer Center, Houston, TX

Background: Most patients with acute myeloid leukemia (AML) experience relapse after initial remission, especially when unable to complete standard consolidation strategies such as high-dose cytarabine or allogeneic stem cell transplantation (SCT). Ideal maintenance therapy consists of the prolonged administration of effective lower intensity agents with the goal of delaying or preventing relapse. Oral azacitidine (QUAZAR AML-001) and 3-day IV decitabine (ECOG ACRIN E2906) have demonstrated efficacy as maintenance. In this phase 1b multi-arm study (NCT05010772), we evaluated the combination of ASTX727 (decitabine/cedazuridine), an oral formulation of decitabine with equivalent AUC to IV decitabine, plus physician choice of an oral targeted agent as personalized maintenance therapy in AML.

Methods: This study enrolled patients ≥ 18 years with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) unable to complete standard therapy and not immediately eligible for SCT. Patients who had received intensive induction (at least 2 cycles of intermediate/high dose cytarabine-based chemotherapy) were enrolled in cohort 1. Patients who had received at least 3 cycles of low-intensity therapy (hypomethylating agent or low-dose cytarabine-based regimens) were eligible for cohort 2. ECOG ≤ 3 and adequate bone marrow function (neutrophils > 0.5 x 109/L, and platelets > 50 x 109/L) were required. All patients received ASTX727 35/100 mg PO on D1-3. Patients were assigned to one of 5 arms per physician decision. Arm A consisted of ASTX727 alone. A second agent was added for the remaining arms (Arm B: venetoclax 400 mg (adjusted for CYP3A4 inhibitor use) PO on D1-5; Arm C: gilteritinib 120 mg PO on D1-28; Arm D: enasidenib 100 mg PO on D1-28; Arm E: ivosidenib 500 mg PO on D1-28). Each arm included an initial safety lead-in cohort using a 3+3 dose de-escalation design in the event of dose limiting toxicity (DLT). Cycles were 28 days and therapy continued for up to 24 cycles. The primary objective was safety/tolerability. Secondary objectives included overall survival (OS) and relapse-free survival (RFS) starting from the time of enrollment. Time-to-event endpoints were censored at the time of SCT.

Results: 31 patients have been enrolled (15 in cohort 1, 16 in cohort 2). 4 patients have been enrolled in arm A, 25 in arm B, 1 in arm C, and 1 in arm D. The median follow-up time is 15.6 m. The median age for the full cohort was 68 years (33-83). ELN 2022 risk was favorable in 13 patients (42%), intermediate in 3 (10%), and adverse in 15 (48%). TP53 mutations were identified in 1 (3%) patient and complex cytogenetics in 3 (10%) patients. 4 (13%) patients had antecedent MDS/MPN and 3 (10%) had therapy-related AML. 9 (29%) patients had detectable measurable residual disease (MRD) at the time of enrollment.

The median number of cycles given is 5 (1-24). No DLT’s have been noted in cycle 1. The most common grade 3/4 adverse events were neutropenia (100%), leukopenia (100%), thrombocytopenia (83%), and anemia (57%). Neutropenic fever occurred in 20% of patients. 1 (3%) patient went off protocol due to toxicity (prolonged thrombocytopenia after 6 cycles) and 1 death occurred while on maintenance.

For the full cohort, the median OS is not reached (NR; 82% at 1 year) and the median RFS is 22.4 months (m) (59% at 1 year). In cohort 1 (intensive induction), the median OS is NR (100% at 1 year) and the median RFS is NR (76% at 1 year). In cohort 2 (low-intensity induction), the median OS is NR (69% at 1 year) and the median RFS is 11.7 m (43% at 1 year). In arm A (ASTX727 alone), the median OS is NR (100% at 1 year) and the median RFS is 16.8 m (50% at 1 year). In arm B (ASTX727 plus venetoclax), the median OS is NR (78% at 1 year) and the median RFS is NR (65% at 1 year).

Of the 9 patients with detectable MRD at enrollment, 2 (22%) became MRD-negative while on maintenance. The median OS was 11.3 m in the MRD-positive patients versus NR in the MRD-negative patients (n=22; p < 0.01). The median RFS was 6.6 m in the MRD-positive patients versus NR in the MRD-negative patients (p < 0.001).

Conclusions: Combination targeted oral maintenance is feasible in AML and demonstrates encouraging RFS. Myelosuppression is universal in subsequent cycles. Prophylactic anti-infectives are encouraged. Further enrollment exploring dose/schedule modifications of ASTX727 on subsequent cycles and longer follow-up are required to confirm the efficacy of these regimens.

Disclosures: Daver: Syndax: Consultancy; Arog: Consultancy; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Celgene: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Astellas: Consultancy, Research Funding; Menarini Group: Consultancy; Shattuck Labs: Consultancy; Trovagene: Research Funding; Novartis: Consultancy; KITE: Research Funding; Agios: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding. Ravandi: Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Syndax: Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Xencor: Research Funding; BMS: Consultancy, Honoraria; Astyex/Taiho: Research Funding. Short: NextCure: Research Funding; BeiGene: Honoraria; Adaptive Biotechnologies: Honoraria; Amgen: Honoraria; GSK: Consultancy, Research Funding; Autolus: Honoraria; Sanofi: Honoraria; Pfizer Inc.: Honoraria; Astellas Pharma, Inc.: Honoraria, Research Funding; Stemline Therapeutics: Research Funding; Novartis: Honoraria; Xencor: Research Funding; Takeda Oncology: Honoraria, Research Funding. Yilmaz: daiichi sankyo: Honoraria, Research Funding. Ohanian: Bio-Path Holdings, Inc.: Consultancy. Maiti: Indapta Therapeutics: Research Funding; Inspirna: Research Funding; CytoMed Therapeutics: Research Funding; Hibercell Inc.: Research Funding; Chimeric Therapeutics: Research Funding; Lin Biosciences: Research Funding. DiNardo: Riegel: Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Loxo: Research Funding; Foghorn: Research Funding; Cleave: Research Funding; ImmuneOnc: Research Funding; Notable Labs: Honoraria; Astellas: Consultancy, Honoraria; AstraZeneca: Honoraria; Rigel: Research Funding; Gilead: Consultancy; Astex: Research Funding; Amgen: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Schrodinger: Consultancy, Honoraria; Immunogen: Honoraria; GSK: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Masarova: MorphoSys: Other: Advisory Board Participant; GSK: Consultancy, Other: Travel support; Cogent: Other: Advisory Board Participant; PharmaEssentia: Other: Advisory Board Participant. Wierda: BMS: Research Funding; GSK: Research Funding; Gilead Sciences: Research Funding; Loxo Oncology: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Novartis: Research Funding; Oncternal Therapeutics: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Numab Therapeutics: Research Funding; Kite: Research Funding; Accutar Biotechnology: Research Funding; Genentech, Inc.: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL); Acerta Pharma: Research Funding; Oncternal Therapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Nurix Therapeutics: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; AbbVie: Research Funding. Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Sasaki: Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Chugai: Other: Lecture fees; Otsuka: Other: Lecture fees; Enliven: Research Funding. Borthakur: Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Garcia-Manero: H3 Biomedicine: Research Funding; Helsinn: Research Funding; Helsinn: Other: Personal fees; Astex: Other: Personal fees; Aprea: Research Funding; Forty Seven: Research Funding; Astex: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Novartis: Research Funding; Amphivena: Research Funding; Genentech: Other: Personal fees; Onconova: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Curis: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Kadia: JAZZ: Research Funding; ASTEX: Research Funding; DrenBio: Consultancy, Research Funding; Servier: Consultancy; Rigel: Honoraria; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Honoraria; Regeneron: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Research Funding; Cellenkos: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Pfizer: Research Funding; Sellas: Consultancy, Research Funding; Amgen: Research Funding.

OffLabel Disclosure: ASTX727 is not currently approved by the FDA for AML.

*signifies non-member of ASH