Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia

Abstract

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

Conflict of interest statement

Conflict-of-interest disclosure: G.J.R. is a consultant/advisor to or was on a data and safety monitoring committee for AbbVie, Actinium, Agios, Amphivena, Argenx, Astex, Astellas, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz Pharmaceuticals (Jazz), Novartis, MEI Pharma, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, and Trovagene; and received research funding from Cellectis. C.D.D. is a consultant/advisor to Agios and Celgene; received honoraria from AbbVie, Agios, Bayer, Celgene, Karyopharm Therapeutics, and MedImmune; and received research funding from AbbVie, Agios, Celgene, and Daiichi Sankyo. 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 Pharma, Celgene, Daiichi Sankyo, Novartis, and Syros. S.d.B. received honoraria from, is a consultant/advisor to, and received research funding and travel expenses from Agios; received honoraria from, and was on a speakers’ bureau for, AbbVie; received honoraria from, and was a consultant/advisor to, Bayer; and received honoraria from, was a consultant/advisor to, and received travel expenses from Carthagenetics, Celgene, FORMA Therapeutics, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, and Servier. A.S.M. is a consultant/advisor to AbbVie, Agios, Astellas, Jazz, and PTC Therapeutics; and was on a speakers’ bureau for Novartis. J.K.A. is a consultant/advisor to AbbVie, Agios, Cancer Expert Now, Daiichi Sankyo, Glycomimetics, Novartis, and Theradex; was on speakers’ bureaus for PeerView, prIME Oncology, and the France Foundation; and received institutional research funding from Agios, Astellas, Boehringer Ingelheim, Celgene, FujiFilm, and Genentech. M.L.A. received research funding from Cephalon. H.P.E. is a consultant/advisor to, was on a speakers’ bureau for, and received research funding from Agios; is a consultant/advisor to, was on a speakers’ bureau for, and provided other services to Celgene; is a consultant/advisor to, provided other services for, and received research funding from GlycoMimetics; is a consultant/advisor to, and received research funding from, Amgen, Daiichi Sankyo, Immunogen, Pfizer, and Seattle Genetics; is a consultant/advisor to, and was on speakers’ bureaus for Incyte, Jazz, and Novartis; is a consultant/advisor to Astellas and Macrogenics; and received research funding from Janssen, Juno Therapeutics, and Takeda. G.N.M. is a consultant/advisor to AbbVie, Amgen, Curis, Forty Seven Inc, Jazz, and NKarta; and received research funding from Agios and Juno Therapeutics. D.A.P. is a consultant/advisor to, and received research funding from, Agios and Pfizer; and is a consultant/advisor to AbbVie, argenx, Celgene, Celyad, Curis, and Servier. A.S.S. was on speakers’ bureaus for Amgen and Celgene. G.L.U. is a consultant/advisor to Curis, Glycomimetics, Jazz, Novartis, Novo Nordisk, and Pfizer; and received travel expenses from Novartis. J.M.W. received research funding from Takeda; was on a speakers’ bureau for, and a consultant/advisor to, Jazz; and is a consultant/advisor to Celgene and Pfizer. A.T.F. is a consultant to Agios, Astellas, Daiichi Sankyo, Celgene, Takeda, Trovagene, Jazz, and Boston Biomedical; and received research funding from Agios, Celgene, Exelixis, and Takeda. H.M.K. received honoraria and research funding from Amgen, ARIAD, Bristol-Myers Squibb, and Pfizer; received honoraria from AbbVie, Immunogen, and Orsenix; and received research funding from Astex and Novartis. M.S.T. has patents with/received royalties from/holds intellectual property (IP) with UpToDate; was a consultant/advisor for, and received research funding from, AbbVie, Arog, Biosight, Cellerant, and Orsenix; received research funding from ADC Therapeutics; and is a consultant/advisor to Bioline Rx, Daiichi Sankyo, DeltaFly Pharma, KAHR Medical, NOHLA Therapeutics, and Rigel. S.C., B.F., H.W., V.Z., S.M.K., and H.L. are employed by and are stockholders in Agios. D.H. is a consultant/advisor to Agios, and was employed by, and a stockholder in, Agios at time of study. D.D., K.E.Y., and S.V.A. were employed by, and stockholders in, Agios at time of study. B.W. is employed by, is a stockholder in, and holds patents with Agios. E.C.A. was employed by, and a stockholder in, Agios at time of study; and provided consulting services to Advance Medical. R.M.S. received honoraria from DAVA, Medscape, Prime Oncology, and Research to Practice; was a consultant/advisor for, and received research funding from, AbbVie, Agios, and Novartis; and was a consultant/advisor to Actinium, Amgen, argenx, Arog, Astellas, AstraZeneca, BioLineRx, Celgene, Cornerstone, Genentech/Roche, Jazz, Macrogenics, Otsuka, Pfizer, Stemline Therapeutics, Takeda, and Trovagene. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment responses and overall survival. (A) Duration of treatment and best overall response (n = 33*). (B) Kaplan-Meier estimate for overall survival (n = 33*). *One patient enrolled in dose-escalation phase was positive for the IDH1-D54N mutation by local testing and was not positive for the IDH1-R132 mutation by the companion diagnostic test; this patient was therefore excluded from the efficacy analyses. CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; HMA, hypomethylating agent; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia-free state; MPN, myeloproliferative neoplasm; NA, not assessed; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2.

Mean ± standard deviation hematologic parameters over time (n = 33*). (A) platelet count, (B) absolute neutrophil count, (C) hemoglobin level, and (D) percentage of bone marrow blasts over time. *One patient enrolled in dose-escalation phase was positive for the IDH1-D54N mutation by local testing and was not positive for the IDH1-R132 mutation by the companion diagnostic test; this patient was therefore excluded from the efficacy analyses.

Figure 3.

Transfusion independence in patients who were transfusion dependent at baseline. Non-CR/CRh responders include patients with CR with incomplete hematologic recovery/incomplete platelet recovery and morphologic leukemia-free state not meeting the criteria for CRh, and patients with PR. Nonresponders include patients with stable disease and progressive disease. *One patient enrolled in dose-escalation phase was positive for the IDH1-D54N mutation by local testing and was not positive for the IDH1-R132 mutation by the companion diagnostic test; this patient was therefore excluded from the efficacy analyses.

Figure 4.

Baseline co-occurring mutations by functional category and clinical response status (n = 33*). RTK pathway mutations were not observed in patients achieving CR/CRh responses (P = .01 by Fisher exact test). *One patient enrolled in dose-escalation phase was positive for the IDH1-D54N mutation by local testing and was not positive for the IDH1-R132 mutation by the companion diagnostic test; this patient was therefore excluded from the efficacy analyses. + indicates patients with treatment duration of >32 months. Red horizontal bars indicate IDH1 mutation clearance. IDH-MC, IDH-mutation clearance.