2017 ASCO Annual Meeting!
Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Type: Oral Abstract Session
Time: Tuesday June 6, 9:45 AM to 12:45 PM
Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study.
Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
2017 ASCO Annual Meeting
J Clin Oncol 35, 2017 (suppl; abstr 7004)
Author(s): Eytan M. Stein, Courtney Denton Dinardo, Daniel Aaron Pollyea, Amir Tahmasb Fathi, Gail J. Roboz, Jessica K. Altman, Richard M. Stone, Ian Flinn, Hagop M. Kantarjian, Robert Collins, Manish R. Patel, Anthony Selwyn Stein, Mikkael A. Sekeres, Ronan T. Swords, Bruno C. Medeiros, Robert D. Knight, Samuel V. Agresta, Stéphane de Botton, Martin S. Tallman; Memorial Sloan Kettering Cancer Center and Weil Cornell Medical College, New York, NY; The University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX; University of Colorado Comprehensive Cancer Center, Aurora, CO; Massachusetts General Hospital and Harvard Medical School, Boston, MA; Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY; Robert H. Lurie Cancer Center of Northwestern University, Feinberg School of Medicine, Chicago, IL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Hematologic Malignancies Research Program, Sarah Cannon Research Institute, Nashville, TN; The University of Texas Southwestern Medical Center, Dallas, TX; Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, FL; City of Hope Comprehensive Cancer Center, Duarte, CA; Cleveland Clinic Taussig Cancer Insitute, Cleveland, OH; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL; Stanford Comprehensive Cancer Center, Stanford, CA; Celgene Corporation, Summit, NJ; Agios Pharmaceuticals, Inc., Cambridge, MA; Institut Gustave Roussy, Villejuif, France; Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical College, New York, NY
Background: Recurrent mutations in isocitrate dehydrogenase 2 (mIDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 protein. Methods: This phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in pts with mIDH2 myeloid malignancies. Safety for all pts and efficacy outcomes for R/R AML pts from the phase 1 dose-escalation and expansion phases are reported. Results: In all, 239 pts received enasidenib. In the dose-escalation (n=113), the MTD was not reached at doses up to 650 mg daily. Median 2HG reductions from baseline were 92%, 90%, and 93% for pts receiving <100 mg, 100 mg, and >100 mg daily, respectively. Enasidenib 100 mg QD was chosen for the expansion phase (n=126) based on PK/PD profiles and demonstrated efficacy. Median number of enasidenib cycles was 5 (range 1–25). Grade 3-4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (ie, retinoic acid syndrome; 7%). For R/R AML pts, overall response rate (ORR) was 40.3%, including 34 (19.3%) complete remissions (CR; Table). Response was associated with cellular differentiation, typically with no evidence of aplasia. Median overall survival (OS) for R/R AML pts was 9.3 months (mos). For pts who attained CR, OS was 19.7 mos. Pts who had received ≥2 prior AML regimens (n=94; 53%) had median OS of 8.0 mos. Conclusions: Enasidenib was well tolerated, induced CRs, and was associated with OS of >9 mos in pts who had failed prior AML therapies. Differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib. Clinical trial information: NCT01915498
|Response||R/R AML Pts|
|100 mg/day |
|CR with incomplete hematologic recovery (CRi)||6.4||6.8|
|Morphologic leukemia-free state (MLFS)||8.0||9.2|
|Partial remission (PR)||6.3||2.8|
|Median response duration||5.8 mos||5.6 mos|