Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Abstract

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

Conflict of interest statement

Conflict-of-interest disclosure: E.M.S. is a stockholder in/has ownership of Auron Therapeutics; is a consultant/advisor to AbbVie, Agios, Astellas, Bayer, BioLineRx, Celgene, Daiichi Sankyo, Genentech, Novartis, Pfizer, PTC Therapeutics, and Syros; received research funding from Agios, Amgen, Bayer, Celgene, and Syros; and received travel expenses from AbbVie, Astellas, BioTheryX, Celgene, Daiichi Sankyo, Novartis, Syndax, and Syros. C.D.D. is a consultant/advisor to AbbVie, Agios, Celgene, Daiichi Sankyo, Jazz, MedImmune, and Notable Labs; and received research funding from AbbVie, Agios, Calithera, Celgene, and Daiichi Sankyo. A.T.F. is a consultant/advisor to Agios, AbbVie, Amgen, Astellas, Boston Biomedical, Celgene (Bristol-Myers Squibb), Daiichi Sankyo, Jazz, Takeda, and Trovagene and received research funding from Agios and Celgene (Bristol-Myers Squibb). A.S.M. is a consultant/advisor to AbbVie, Agios, Astellas, Jazz, and PTC Therapeutics. K.W.P. is an advisor to Agios, AbbVie, Astellas, Boston Biomedical, and Celgene/Bristol-Myers Squibb and received institutional research funding from AbbVie, Agios, Astellas, and Takeda. M.R.S. received research support from Astex, Incyte, Sunesis, Takeda, and TG Therapeutics; is a stockholder in/has ownership of Karyopharm; is a consultant/advisor to AbbVie, Bristol-Myers Squibb, Celgene, Merck, Ryvu, Sierra Oncology, and TG Therapeutics; and has patents with/received royalties from Boehringer Ingelheim. A.S.S. is on a speakers’ bureau for Amgen, Celgene, and Stemline and is an advisor to Amgen. R.M.S. is on a steering committee for Celgene; is an advisor to AbbVie, Actinium, Agios, Amgen, Astellas, BioLineRx, Celgene, Daiichi Sankyo, ElevateBio, GEMoaB, Janssen, MacroGenics, Novartis, Syndax, Takeda, and Trovagene; received clinical research funding from AbbVie, Agios, and Syndax; and is on data safety monitoring boards for Argenx, Celgene, and Takeda. E.S.W. is an advisor to Jazz, Pfizer, and Shionogi. H.D. is a consultant to/received honoraria from AbbVie, Agios, Amgen, Astellas, Astex, Celgene, Helsinn, Janssen, Jazz, Novartis, Oxford Biomedicals, and Roche and received institutional clinical research funding from Amgen, AROG, Bristol-Myers Squibb, Celgene, Jazz, Pfizer, and Sunesis. D.A.P. is a consultant to AbbVie, Agios, Amgen, Celgene, Celyad, Daiichi Sankyo, Forty Seven, Gilead, Pfizer, and Takeda; and received research funding from AbbVie and Pfizer. J.K.M. is on a speakers’ bureau for Amgen, Celgene, Jazz, and Takeda; received honoraria from Celgene; is a consultant to Jazz, Pfizer, and Takeda; and is a stockholder in/has ownership in COTA. O.O. is an advisor to AbbVie, Celgene, and Impact Biomedicines and received institutional clinical research funding from AbbVie, Agios, AstraZeneca, Celgene, Daiichi Sankyo, Incyte, NS Pharma, and OncoTherapy Science. B.L. is an advisor to AbbVie, Agios, AIMM Therapeutics, Astellas, Astex, Celgene, Clear Creek Bio, F. Hoffman-La Roche, Frame, GEMoaB, and Oxford Biomedical. G.J.O. is a consultant to AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Jazz, Novartis, Pfizer, and Roche and received research funding from BD, Celgene, Genentech, Johnson & Johnson, and Novartis. P.A.P. received honoraria from DAVA Oncology and France Foundation and is a member of an entity's board of directors/advisory committees/speakers’ bureau for Celgene. M.R. is involved with the provision of services for Auron Therapeutics, Celgene, and Physicians' Education Resource and is a stockholder in/has ownership of Auron Therapeutics. M.G.F. is an employee of and stockholder in/has ownership of Bristol-Myers Squibb. F.L. is an employee of and stockholder in/has ownership of Celgene International. A.F. is an employee of Bristol-Myers Squibb. S.N., S.C., C.A., and M.C. are employees of and stockholders in/have ownership of Agios. B.F., H.W., and L.H. were employees of and stockholders in/had ownership of Agios at the time of the study. B.W. is an employee of, stockholder in/has ownership of, and received patents/royalties from Agios. H.M.K. received research funding from AbbVie, Agios, Amgen, ARIAD, Astex, Bristol-Myers Squibb, Cyclacel, Daiichi Sankyo, ImmunoGen, Jazz, Novartis, and Pfizer and received honoraria from AbbVie, Actinium, Agios, Amgen, Pfizer, and Takeda. M.S.T. received patents/royalties from UpToDate; is a consultant/member of an entity's board of directors/advisor to AbbVie, BioLineRx, Daiichi Sankyo, Delta-Fly Pharma, Jazz, KAHR, Nohla, Oncolyze, Orsenix, Rigel, Roche, and Tetraphase; and received research funding from AbbVie, ADC Therapeutics, BioSight, Cellerant, and Orsenix. C.S.S. declares no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Disposition of the study population. ARA-C, cytarabine; DNR, daunorubicin; IDR, idarubicin.

Figure 2.

Overall survival in the FAS set. Patients not censored at the time of HSCT.

Figure 3.

Baseline mutational landscape and best overall clinical responses. Each column represents an individual patient, organized by best overall response. Genes (rows) are grouped by biological pathway. A blue box indicates the detection of a known or likely oncogenic variant in at least 1 sample type (peripheral blood and/or bone marrow). NA, not assessed; NE, not evaluable; PD, progressive disease; RTK, receptor tyrosine kinase; SD, stable disease.

Figure 4.

Paired sample analysis of mutations by NGS at screening and end of induction. (A) Ivosidenib-treated patients with a best response of CR/CRi/CRp only, n = 31, Personalis ACE Cancer Panel. (B) Enasidenib-treated patients with a best response of CR/CRi/CRp only, n = 28, Archer VariantPlex Core Myeloid panel. Values under each bar denote the number of patients with a mutation detected at baseline and end of induction, and the mutation clearance rate (%) for each gene.