• Courtney D DiNardo, Eytan M Stein, Stéphane de Botton, Gail J Roboz, Jessica K Altman, Alice S Mims, Ronan Swords, Robert H Collins, Gabriel N Mannis, Daniel A Pollyea, Will Donnellan, Amir T Fathi, Arnaud Pigneux, Harry P Erba, Gabrielle T Prince, Anthony S Stein, Geoffrey L Uy, James M Foran, Elie Traer, Robert K Stuart, Martha L Arellano, James L Slack, Mikkael A Sekeres, Christophe Willekens, Sung Choe, Hongfang Wang, Vickie Zhang, Katharine E Yen, Stephanie M Kapsalis, Hua Yang, David Dai, Bin Fan, Meredith Goldwasser, Hua Liu, Sam Agresta, Bin Wu, Eyal C Attar, Martin S Tallman, Richard M Stone, and Hagop M Kantarjian.
• From the University of Texas M.D. Anderson Cancer Center, Houston (C.D.D., H.M.K.); Memorial Sloan Kettering Cancer Center (E.M.S., M.S.T.) and Weill Cornell Medical College (G.J.R.), New York; Institut Gustave Roussy, Villejuif (S.B., C.W.), and Centre Hospitalier Universitaire Bordeaux, Bordeaux (A.P.) - both in France; Northwestern University, Chicago (J.K.A.); Ohio State University Wexner Medical Center, Columbus (A.S.M.); Sylvester Comprehensive Cancer Center, University of Miami, Miami (R.S.); University of Texas Southwestern Medical Center, Dallas (R.H.C.); University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco (G.N.M.), and City of Hope Medical Center, Duarte (A.S.S.) - both in California; University of Colorado School of Medicine, Aurora (D.A.P.); Sarah Cannon Research Institute, Nashville (W.D.); Massachusetts General Hospital Cancer Center (A.T.F.) and Dana-Farber Cancer Institute (R.M.S.), Boston, and Agios Pharmaceuticals, Cambridge (S.C., H.W., V.Z., K.E.Y., S.M.K., H.Y., D.D., B.F., M.G., H.L., S.A., B.W., E.C.A.) - all in Massachusetts; University of Alabama at Birmingham, Birmingham (H.P.E.); Johns Hopkins University, Baltimore (G.T.P.); Washington University School of Medicine, St. Louis (G.L.U.); Mayo Clinic, Jacksonville, FL (J.M.F.); Oregon Health and Science University Knight Cancer Institute, Portland (E.T.); Hollings Cancer Center, Medical University of South Carolina, Charleston (R.K.S.); Winship Cancer Institute of Emory University, Atlanta (M.L.A.); Mayo Clinic, Phoenix, AZ (J.L.S.); and Cleveland Clinic, Cleveland (M.A.S.).
• N. Engl. J. Med. 2018 Jun 21; 378 (25): 2386-2398.

BackgroundMutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1.MethodsWe conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up.ResultsOverall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment.ConclusionsIn patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

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