Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study
Authors: DiNardo Courtney D. , Schuh Andre C. , Stein Eytan M. , Fernandez Pau Montesinos , Wei Andrew , De Botton Stephane , Zeidan Amer M. , Fathi Amir T. , Quek Lynn , Kantarjian Hagop M. , Frattini Mark G. , Lersch Frederik , Gong Jing , Franovic Aleksandra , MacBeth Kyle , Vyas Paresh , Döhner Hartmut 
Published: February 2020

Background: Mutations in IDH2 occur in 8-19% of patients (pts) with AML. Enasidenib (ENA; AG-221) is an oral, small-molecule inhibitor of mutant IDH2 (mIDH2) that promotes myeloid cell differentiation. ENA is approved in the US for use in adult pts with relapsed/refractory mIDH2 AML. Azacitidine (AZA) is a hypomethylating agent that prolongs survival vs. conventional care regimens in older unfit pts with newly diagnosed (ND) AML. AZA promotes DNA hypomethylation by inhibiting DNA methyltransferases. ENA indirectly reduces DNA methylation by suppressing the oncometabolite, 2-hydroxyglutarate (2-HG), thereby restoring function to α-ketoglutarate-dependent TET family enzymes, among other substrates. In vitro, combination ENA + AZA enhances cell differentiation. This is the first report of interim outcomes from the randomized, phase II portion of an ongoing, open-label, phase I/II study of ENA + AZA vs. AZA monotherapy (AZA-only) in pts with mIDH2 ND-AML who are not candidates for intensive chemotherapy (IC) (NCT02677922).
Methods: Adult pts with mIDH2 ND-AML who were ineligible to receive IC and had ECOG PS scores ≤2 were randomized in a 2:1 ratio to receive ENA + AZA or AZA-only in repeated 28-day cycles. All pts receive SC AZA 75 mg/m2/day for the first 7 days of each treatment (Tx) cycle; pts randomized to ENA + AZA also receive continuous ENA 100 mg QD.
The primary endpoint is overall response rate (ORR), which includes complete remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS), per modified IWG 2003 AML response criteria. P values for response comparisons between Tx arms were derived using chi-square test. Duration of response (DOR) was estimated by Kaplan-Meier method. mIDH2 variant allele frequencies (VAF) in bone marrow mononuclear cells (BMMCs) were assessed by digital PCR.
Results: Between Oct. 2016 and Aug. 2018, 101 pts were randomized to receive ENA + AZA (n=68) or AZA-only (n=33). Median ages were 74 years (range 62-85) in the ENA + AZA arm and 75 years (57-85) in the AZA-only arm. Among pts with available data, 78% in the ENA + AZA arm (43/55) and 90% (19/21) in the AZA-only arm had intermediate-risk cytogenetics, respectively, and 18% and 10% had poor-risk cytogenetics. At data cutoff (Feb. 2019), 39 pts were still receiving their randomized Tx. Most common reasons for study discontinuation in the ENA + AZA and AZA-only arms were death (31% and 27%, respectively) and pt decision (4% and 12%). Two pts in the ENA + AZA arm and 1 pt in the AZA-only arm proceeded to transplant. Median number of Tx cycles was 8 (range 1-24) in the ENA + AZA arm and 6 (1-22) in the AZA-only arm; 27% and 19% of pts, respectively, received ≥12 Tx cycles.
Response rates were significantly higher with combination treatment vs. AZA alone: ORRs were 68% vs. 42%, respectively (P=0.0155), and CR rates were 50% vs. 12% (P=0.0002) (Table). Median DOR was not reached with ENA + AZA and was 10.2 months in the AZA-only arm (P=0.13). Maximal mIDH2 VAF suppression from baseline was significantly greater with ENA + AZA vs. AZA-only (median -69.3% vs. -14.1%, respectively; P=0.0004).
Tx-related grade 3-4 adverse events occurring in ≥10% of pts in the combination arm were neutropenia (34%), thrombocytopenia (34%), anemia (21%), febrile neutropenia (12%), and IDH differentiation syndrome (IDH-DS; 10%); these events occurred in 19%, 19%, 22%, 13%, and 0% of pts in the AZA-only arm. Rate of Tx-related grade 3-4 infections was 16% in the ENA + AZA arm and 31% in the AZA-only arm. In all, 12 pts (18%) in the ENA + AZA arm experienced IDH-DS (any grade) at a median of 37 days. In the first 60 days, 5 deaths (7%) were reported in the ENA + AZA arm (3 due to infectious complications and 2 due to possible IDH-DS) and 1 death (3%) was reported in the AZA-only arm due to progressive disease.
Conclusions: ENA + AZA was associated with significantly improved complete remission and overall response rates and significant mIDH2 VAF reductions compared with AZA-only. Combination Tx was generally well tolerated, with a safety profile similar to that reported for either monotherapy. An updated data cutoff that includes at least 1 year of follow-up for all pts will be presented at the conference. Updated data will include overall survival, event-free survival, and comprehensive analyses of 2-HG and co-mutation dynamics.

Disclosures
DiNardo: syros: Honoraria; jazz: Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Schuh:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stein:Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Fernandez:Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. De Botton:Novartis: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Pierre Fabre: Consultancy; Daiichi: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Servier: Consultancy; Syros: Consultancy; Janssen: Consultancy; Forma: Consultancy, Research Funding; Bayer: Consultancy; Agios: Consultancy, Research Funding. Zeidan:ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Quek:Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. Kantarjian:Immunogen: Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Frattini:Celgene Corporation: Employment, Equity Ownership. Lersch:Celgene: Employment, Equity Ownership. Gong:Celgene: Employment, Equity Ownership. Franovic:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Vyas:Celgene: Research Funding, Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Abbvie: Speakers Bureau; Pfizer: Speakers Bureau; Astellas: Speakers Bureau. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding.