A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

"Conflict-of-interest disclosure: S.F.C. is a consultant for and holds equity interest in Imago BioSciences. G.J.S. has commercial interests in Bristol Myers Squibb (BMS), Amgen, and Johnson & Johnson (J&J); has received fees from AbbVie, Agios, Amgen, Astellas, BMS, Incyte, Janssen, Jazz, Karyopharm, Kite, Pharmacyclics, Sanofi/Genzyme, and Stemline; and has received research funding from 10.13039/100006483AbbVie, Actinium, Actuate, Arog, Astellas, AltruBio, AVM Bio, BMS/10.13039/100006436Celgene, Celator, 10.13039/100025208Constellation, 10.13039/501100002973Daiichi-Sankyo, Deciphera, Delta-Fly, Forma, FujiFilm, Gamida, Genentech-Roche, GlycoMimetics, Geron, 10.13039/100017655Incyte, Karyopharm, Kiadis, Kite/10.13039/100005564Gilead, Kura, Marker, Mateon, Onconova, 10.13039/100004319Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, Trovagene, 10.13039/100016471Agios, 10.13039/100002429Amgen, Jazz, 10.13039/100018187Orca, Ono-UK, and 10.13039/100004336Novartis. J.M.F. has received research funding from Takeda/Millennium. P.P. has served on the advisory board of Agios Pharmaceuticals and is currently an employee of Servier. J.-A.V. is an employee of Foundation Medicine Inc with equity in Roche. B.J.D. reports serving on the scientific advisory board of Adela Bio, Aileron Therapeutics, and Therapy Architects/ALLCRON (inactive) as well as Cepheid, Celgene, DNA SEQ, Nemucore Medical Innovations, Novartis, RUNX1 Research Program, and Vivid Biosciences (inactive); reports serving on scientific advisory board and owning stocks in Aptose Biosciences, Blueprint Medicines, Enliven Therapeutics, Iterion Therapeutics, Grail, and Recludix Pharma; serving on the board of directors and owning stocks in Amgen and Vincerx Pharma; serving on the board of directors in Burroughs Wellcome Fund and CureOne; being a member on the joint steering committee of Beat AML LLS; being a member on the advisory committee of Multicancer Early Detection Consortium; is the founder of VB Therapeutics; reports sponsored research agreements with Enliven Therapeutics and Recludix Pharma; clinical trial funding from 10.13039/100004336Novartis and 10.13039/100004325AstraZeneca; royalties from patent 6958335 (Novartis exclusive license) and Oregon Health and Science University (OHSU) and Dana-Farber Cancer Institute (1 Merck exclusive license, 1 CytoImage, Inc exclusive license, and 1 Sun Pharma Advanced Research Company nonexclusive license); and holds US patents 4326534, 6958335, 7416873, 7592142, 10473667, 10664967, and 11049247. A.S.M. has served on the advisory boards of Jazz Pharmaceuticals, AbbVie/Genentech, Astellas Pharma, PTC Therapeutics, Novartis, Agios Pharmaceuticals and Syndax Pharmaceuticals. U.B. has been a consultant for Genentech, Daiichi Sankyo, Takeda, Pfizer, AbbVie/Genentech, and Novartis. J.C.B. is a current equity holder in Vincerx Pharma Inc (a publicly traded company); holds membership on the board of directors or advisory committees of Vincerx, Newave, and Orange Grove Bio; and reports being a consultant or receiving honoraria from Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, and Syndax. R.L.L. is on the supervisory board of Qiagen; is a scientific adviser to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics, and Isoplexis; receives research support from and has consulted for Celgene and Roche; has consulted for Incyte, Janssen, Astellas, MorphoSys, and Novartis; and has received honoraria from AstraZeneca, Roche, Lilly, and Amgen for invited lectures and from Gilead for grant reviews. E.M.S. has served on the advisory boards of Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Novartis, Amgen, Seattle Genetics, Syros Pharmaceuticals, Syndax Pharmaceuticals, Agios Pharmaceuticals, and Celgene, and is an equity holder in Auron Therapeutics. The remaining authors declare no competing financial interests."

"S.F.C. was supported by a Young Investigator Award from the 10.13039/100008884Edward P. Evans Foundation and a Career Development Award from the National Cancer Institute (K08 CA241371-01A1). Studies supported by Memorial Sloan Kettering core facilities were supported in part by 10.13039/100007052Memorial Sloan Kettering Cancer Center Support Grant/Core grant P30 15 CA008748. R.L.L. is supported by 10.13039/100000054National Cancer Institute grants P01 CA108671 and R35197594, as well as a Leukemia & Lymphoma Society Specialized Center of Research grant. Sequencing efforts were funded and performed by 10.13039/100020387ArcherDx."

"Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998."