Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

Abstract

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.

Conflict of interest statement

Conflict-of-interest disclosure: E.M.S. received grants and personal fees from Celgene Corporation and Agios Pharmaceuticals, Inc. C.D.D. received personal fees and clinical research support from Agios Pharmaceuticals, Inc. and clinical research support from Celgene Corporation. D.A.P. served on the advisory board for Pfizer, Karyopharm, Celgene Corporation, and Agios Pharmaceuticals, Inc. and received grants from Agios Pharmaceuticals, Inc. A.T.F. consulted for and received clinical trial support from Celgene Corporation and Seattle Genetics; served on advisory boards for Merck, Juno, Tolero, and Bexalata; and received clinical trial support from Takeda and Exelixis. G.J.R. consulted for Agios Pharmaceuticals, Inc., Celgene Corporation, Amgen, Amphivena, Astex, AstraZeneca, Celator, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, and Sunesis; and received research support from Cellectis. J.K.A. received personal fees from Syros, Janssen Pharmaceuticals, Novartis, Seattle Genetics, Spectrum, Ariad, Bristol-Myers Squibb, and Celgene Corporation; and funds to institution for trial participation from MethylGene Inc., Boehringer Ingelheim, Astellas, Agios Pharmaceuticals, Bristol-Myers Squibb, CSL Limited, Cyclacel, Epizyme, Genentech, Pfizer, BioLineRX, and Talon Therapeutics. R.M.S. served on an advisory board for Agios Pharmaceuticals, Inc., Novartis, Celgene Corporation, AbbVie, Karyopharm, Arog, Jansen, Celator/Jazz, Seattle Genetics, and Roche/Genetech; and served on data and safety monitoring boards for Celgene Corporation and Sunesis. D.J.D. served on the advisory board for Celgene Corporation. R.L.L. received research support from Celgene Corporation and serves on the supervisory board for Qiagen. I.W.F. received grants from Agios Pharmaceuticals, Inc., Acerta, Beigene, Celgene Corporation, Constellation, Curls, FortySeven, Genentech, Gilead, ImmunoGen, Incyte, Infinity, Janssen, Kite, Merck, Novartis, OncoMed, Pfizer, Portola, Seattle Genetics, Takeda, TG Therapeutics, and Trillium. R.C. received clinical research funding from Agios Pharmaceuticals, Inc. and Celgene Corporation. A.S. consulted for Amgen and Stemline. M.A.S. served on the advisory board for Celgene Corporation. R.T.S. received grants from Takeda and personal fees from Novartis, Agios Pharmaceuticals, Inc., and Celgene Corporation. B.C.M. served on advisory boards for Agios Pharmaceuticals, Inc. and Celgene Corporation. C.W. received grants from Agios Pharmaceuticals, Inc. A.T., Q.X., and R.D.K. are employees and stockholders of Celgene Corporation. K.E.Y. and S.A. are employees of Agios Pharmaceuticals, Inc. S.d.B. received personal fees from Agios Pharmaceuticals, Inc., Celgene Corporation, Novartis, Pfizer and Servier. The remaining authors declare no competing financial interests.

© 2017 by The American Society of Hematology.

Figures

Figure 1.

Evolution of response during treatment of responding patients (n = 71). Bars reflect responses at each cycle. CR, complete response; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; MLFS, morphologic leukemia-free state; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2.

Morphologic evidence of myeloid differentiation during enasidenib treatment. (A) Bone marrow (BM) blasts at screening (left). By cycle 3 day 1 (right), maturing forms including promyelocytes and myelocytes have largely replaced the immature myeloblasts, without initial marrow aplasia or hypoplasia at cycle 1 day 15 (middle). (B) Fluorescence in situ hybridization evidence of myeloid differentiation during enasidenib treatment. At screening, this patient with an IDH2-R140Q mutation had trisomy 8 in the majority of myeloblasts. By cycle 2 day 1, mature forms appeared with persistence of trisomy 8 in promyelocytes and mature granulocytes. In contrast, cells in the lymphoid compartment have a normal complement of chromosome 8.

Figure 3.

Mean (± standard error) platelet count, absolute neutrophil count, hemoglobin, and bone marrow blasts over time in patients with relapsed/refractory AML treated with enasidenib.

Figure 4.

Overall survival. (A) Overall survival among all patients with relapsed/refractory (R/R) AML. (B) Overall survival among patients with relapsed/refractory AML in complete remission (CR), patients with a non-CR hematologic response, or no response. NE, not evaluated.