ENASIDENIB PLUS AZACITIDINE SIGNIFICANTLY IMPROVES COMPLETE REMISSION AND OVERALL RESPONSE RATES VERSUS AZACITIDINE MONOTHERAPY IN MUTANT-IDH2 NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (ND-AML)
Author(s): ,
Courtney DiNardo
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Andre Schuh
Affiliations:
Princess Margaret Cancer Centre,Toronto,Canada
,
Eytan Stein
Affiliations:
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College,New York,United States
,
Pau Montesinos
Affiliations:
Hospital Universitari i Politecnic La Fe,Valencia,Spain;CIBERONC, Instituto de Salud Carlos III,Madrid,Spain
,
Andrew Wei
Affiliations:
The Alfred Hospital and Monash University,Melbourne,Australia
,
Stéphane de Botton
Affiliations:
Gustave Roussy,Villejuif,France
,
Amer Zeidan
Affiliations:
Yale School of Medicine,New Haven,United States
,
Amir Fathi
Affiliations:
Harvard Medical School and Massachusetts General Hospital Cancer Center,Boston,United States
,
Lynn Quek
Affiliations:
Oxford Biomedical Research Centre and Oxford University Hospitals NHS Foundation Trust,Oxford,United Kingdom
,
Hagop Kantarjian
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Mark Frattini
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Frederik Lersch
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Jing Gong
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Aleksandra Franovic
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Paresh Vyas
Affiliations:
Oxford Biomedical Research Centre and Oxford University Hospitals NHS Foundation Trust,Oxford,United Kingdom
Hartmut Döhner
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
EHA Library. DiNardo C. 06/12/20; 294959; S139
Courtney DiNardo
Courtney DiNardo
Contributions
Abstract

Abstract: S139

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: AML randomized trials

Background
Enasidenib (ENA) is an oral, small-molecule inhibitor of mutant IDH2 (mIDH2) proteins that reduces DNA methylation by suppressing the oncometabolite, 2-hydroxyglutarate (2-HG), thereby restoring function to α-ketoglutarate-dependent TET family enzymes and other substrates. Azacitidine (AZA) is a hypomethylating agent that reduces DNA methylation by inhibiting DNA methyltransferases. ENA and AZA each induce an overall response rate (ORR) of ~30% and a complete remission (CR) rate of ~20% in ND-AML. In vitro, combining ENA + AZA enhanced single-agent effects on releasing differentiation block. The randomized phase II portion of the open-label phase I/II AG-221-AML-005 study compared combination ENA + AZA vs. AZA monotherapy (AZA Only) in patients (pts) with mIDH2 ND-AML who were not eligible for intensive chemotherapy (NCT02677922).

Aims
Evaluate the efficacy, safety, and effects on 2-HG and mIDH2 VAF of combination ENA + AZA vs. AZA Only.

Methods
Pts aged ≥18 yrs with mIDH2 ND-AML, ECOG PS ≤2 and intermediate- or poor-risk cytogenetics were randomized 2:1 to ENA + AZA or AZA Only in 28-day (d) cycles. All pts received SC AZA 75 mg/m2/d x 7 d/cycle; pts randomized to ENA + AZA also received ENA 100 mg QD. The primary endpoint was ORR, ie, the proportion of pts achieving CR, CR with incomplete count recovery (CRi/CRp), partial remission (PR), or morphologic leukemia-free state (MLFS) (IWG 2003 criteria). Other endpoints included duration of response (DOR), overall survival (OS), event-free survival (EFS), and changes in 2-HG levels and mIDH2 VAF.

Results
In all, 101 pts were randomized to ENA + AZA (n=68) or AZA Only (n=33). Median age was 75 yrs (57–85); most pts (83%) had intermediate-risk cytogenetics. 21 pts in the ENA + AZA arm and 1 in the AZA Only arm were ongoing at data cutoff (Aug 2019). The most common reason for discontinuation was disease progression (ENA + AZA 31%, AZA Only 52%). Median number treatment (Tx) cycles was 10 (1–26) in the ENA + AZA arm and 6 (1–28) in the AZA Only arm. In the AZA Only arm, 7 pts (21%) received subsequent Tx with ENA after discontinuing AZA.

ORR and CR rate were significantly improved with ENA + AZA vs. AZA Only (Table), with a median DOR of 24.1 mo in the ENA + AZA arm vs. 12.1 mo in the AZA Only arm. Median OS was 22 mo in both arms (HR 0.99 [95%CI 0.52, 1.87]; P = 0.97). Median EFS was 17.2 and 10.8 mo in the ENA + AZA and AZA Only arms, respectively (HR 0.59 [95%CI 0.30, 1.17]; P = 0.13) (Figure). ENA + AZA was associated with significantly greater maximal changes from baseline (BL) in mIDH2 VAF (median –83.4% vs. –17.7% with AZA Only; P < 0.01) and 2-HG levels (median –97.8% vs. –54.3%; P < 0.01). No BL co-mutation predicted primary resistance.

Common Tx-related grade 3–4 adverse events in the ENA + AZA arm were thrombocytopenia (37%), neutropenia (35%), anemia (19%), and febrile neutropenia (15%); these occurred in 19%, 22%, 22%, and 16% of pts in the AZA Only arm. Grade 3–4 infections occurred in 18% of ENA + AZA pts and 31% of AZA Only pts. IDH differentiation syndrome was reported for 12 pts (18%) in the ENA + AZA arm.

Conclusion
Combination ENA + AZA resulted in significantly improved response rates vs. AZA monotherapy and was generally well-tolerated in pts with mIDH2 ND-AML. ENA + AZA also led to deep reductions in 2-HG concentrations and mIDH2 VAF vs. AZA Only. Median OS in the AZA Only arm was longer than previous reports of AZA in pts with mIDH2 ND-AML. The impact of subsequent Tx on OS and EFS, and new translational data, will be presented at the meeting.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): Acute myeloid leukemia, Azacitidine, Enasidenib

Abstract: S139

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: AML randomized trials

Background
Enasidenib (ENA) is an oral, small-molecule inhibitor of mutant IDH2 (mIDH2) proteins that reduces DNA methylation by suppressing the oncometabolite, 2-hydroxyglutarate (2-HG), thereby restoring function to α-ketoglutarate-dependent TET family enzymes and other substrates. Azacitidine (AZA) is a hypomethylating agent that reduces DNA methylation by inhibiting DNA methyltransferases. ENA and AZA each induce an overall response rate (ORR) of ~30% and a complete remission (CR) rate of ~20% in ND-AML. In vitro, combining ENA + AZA enhanced single-agent effects on releasing differentiation block. The randomized phase II portion of the open-label phase I/II AG-221-AML-005 study compared combination ENA + AZA vs. AZA monotherapy (AZA Only) in patients (pts) with mIDH2 ND-AML who were not eligible for intensive chemotherapy (NCT02677922).

Aims
Evaluate the efficacy, safety, and effects on 2-HG and mIDH2 VAF of combination ENA + AZA vs. AZA Only.

Methods
Pts aged ≥18 yrs with mIDH2 ND-AML, ECOG PS ≤2 and intermediate- or poor-risk cytogenetics were randomized 2:1 to ENA + AZA or AZA Only in 28-day (d) cycles. All pts received SC AZA 75 mg/m2/d x 7 d/cycle; pts randomized to ENA + AZA also received ENA 100 mg QD. The primary endpoint was ORR, ie, the proportion of pts achieving CR, CR with incomplete count recovery (CRi/CRp), partial remission (PR), or morphologic leukemia-free state (MLFS) (IWG 2003 criteria). Other endpoints included duration of response (DOR), overall survival (OS), event-free survival (EFS), and changes in 2-HG levels and mIDH2 VAF.

Results
In all, 101 pts were randomized to ENA + AZA (n=68) or AZA Only (n=33). Median age was 75 yrs (57–85); most pts (83%) had intermediate-risk cytogenetics. 21 pts in the ENA + AZA arm and 1 in the AZA Only arm were ongoing at data cutoff (Aug 2019). The most common reason for discontinuation was disease progression (ENA + AZA 31%, AZA Only 52%). Median number treatment (Tx) cycles was 10 (1–26) in the ENA + AZA arm and 6 (1–28) in the AZA Only arm. In the AZA Only arm, 7 pts (21%) received subsequent Tx with ENA after discontinuing AZA.

ORR and CR rate were significantly improved with ENA + AZA vs. AZA Only (Table), with a median DOR of 24.1 mo in the ENA + AZA arm vs. 12.1 mo in the AZA Only arm. Median OS was 22 mo in both arms (HR 0.99 [95%CI 0.52, 1.87]; P = 0.97). Median EFS was 17.2 and 10.8 mo in the ENA + AZA and AZA Only arms, respectively (HR 0.59 [95%CI 0.30, 1.17]; P = 0.13) (Figure). ENA + AZA was associated with significantly greater maximal changes from baseline (BL) in mIDH2 VAF (median –83.4% vs. –17.7% with AZA Only; P < 0.01) and 2-HG levels (median –97.8% vs. –54.3%; P < 0.01). No BL co-mutation predicted primary resistance.

Common Tx-related grade 3–4 adverse events in the ENA + AZA arm were thrombocytopenia (37%), neutropenia (35%), anemia (19%), and febrile neutropenia (15%); these occurred in 19%, 22%, 22%, and 16% of pts in the AZA Only arm. Grade 3–4 infections occurred in 18% of ENA + AZA pts and 31% of AZA Only pts. IDH differentiation syndrome was reported for 12 pts (18%) in the ENA + AZA arm.

Conclusion
Combination ENA + AZA resulted in significantly improved response rates vs. AZA monotherapy and was generally well-tolerated in pts with mIDH2 ND-AML. ENA + AZA also led to deep reductions in 2-HG concentrations and mIDH2 VAF vs. AZA Only. Median OS in the AZA Only arm was longer than previous reports of AZA in pts with mIDH2 ND-AML. The impact of subsequent Tx on OS and EFS, and new translational data, will be presented at the meeting.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): Acute myeloid leukemia, Azacitidine, Enasidenib

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