PS1025 IVOSIDENIB (AG‐120) INDUCES DURABLE REMISSIONS AND TRANSFUSION INDEPENDENCE IN PATIENTS WITH IDH1‐MUTANT NEWLY‐DIAGNOSED AML: UPDATED RESULTS FROM A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY
Authors: Roboz G.J. , DiNardo C.D. , Stein E.M. , de Botton S. , Mims A.S. , Prince G.T. , Altman J.K. , Arellano M.L. , Donnellan W. , Erba H.P. , Mannis G.N. , Pollyea D.A. , Stein A.S. , Uy G.L. , Watts J.M. , Fathi A.T. , Kantarjian H.M. , Tallman M.S. , Choe S. , Dai D. , Fan B. , Wang H. , Zhang V. , Yen K.E. , Kapsalis S.M. , Hickman D. , Liu H. , Agresta S. , Wu B. , Attar E.C. , Stone R.M. 
Published: June 2019

Background:Isocitrate dehydrogenase 1 (IDH1) mutations are reported in 6–10% of patients (pts) with acute myeloid leukemia (AML). Ivosidenib (IVO, AG‐120) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory AML. IVO suppresses production of the oncometabolite 2‐hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.Aims:To assess the safety and efficacy of single‐agent IVO in pts with newly diagnosed (ND) AML who were not eligible for standard therapy and enrolled in the first‐in‐human, phase 1, dose escalation and expansion study of pts with mIDH1 advanced hematologic malignancies (NCT02074839).Methods:The study is ongoing; enrollment was completed on May 8, 2017. In dose escalation, pts received IVO orally (dose range, 200–1200 mg daily) in 28‐day cycles; 500 mg once daily (QD) was selected for expansion. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial remission + morphologic leukemia‐free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count >0.5 × 109/L (500/μL) and platelet count >50 × 109/L (50,000/μL). Exploratory biomarker assessments included baseline co‐occurring mutations (next‐generation sequencing) and mIDH1 variant allele frequency (VAF) (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02–0.04%). We present data for all pts with ND AML not eligible for standard therapy whose starting dose was 500 mg QD (n = 34); efficacy is reported for pts confirmed mIDH1‐positive by the companion diagnostic test (n = 33).Results:Baseline characteristics of the 34 pts with ND AML were: 19 men/15 women; median age 76.5 years (range 64–87); 56% were ≥75 years of age; 76% had secondary AML and 53% had prior MDS; 47% had ≥1 hypomethylating agent (HMA) for an antecedent hematologic disorder. As of Nov 2, 2018, 7 of 34 (21%) pts remained on treatment; 3 (9%) had discontinued treatment for allogeneic stem cell transplant. Median duration of exposure to IVO was 4.3 months (range 0.3–40.9). Adverse events (AEs) of any grade and causality occurring in ≥25% of pts were diarrhea (53%), fatigue (47%), nausea (38%), decreased appetite (35%), leukocytosis (26%), anemia (26%), thrombocytopenia (26%), and peripheral edema (26%). Most AEs were grade 1–2 and reported as unrelated to treatment. IDH differentiation syndrome (DS) was seen in 6 of 34 (18%) pts, and was grade ≥3 in 3 (9%); IVO was held owing to DS in 3 pts. QT prolongation was seen in 6 pts (18%). CR rate was 30% (95% CI 16%, 49%), CR+CRh rate 42% (95% CI 26%, 61%), and ORR 55% (95% CI 36%, 72%). Median durations of CR, CR+CRh, and overall response were not estimable (95% CI lower bound 4.2, 4.6, and 4.6 months, respectively); 12‐month response durations were 78%, 62%, and 63%, respectively. Of 21 pts who were transfusion dependent at baseline, 43% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 30 pts: mIDH1 clearance was seen in 9 of 14 pts achieving CR+CRh (5 of 10 with CR and 4 of 4 with CRh). The relationship between baseline co‐occurring mutations and response will be presented.Summary/Conclusion:IVO monotherapy was well tolerated in pts with mIDH1 ND AML, and induced durable remissions and transfusion independence in a molecularly defined, elderly pt population with poor prognosis and high rates of secondary AML and prior HMA exposure.