Ivosidenib (IVO; AG-120) in IDH1-mutant newly-diagnosed acute myeloid leukemia (ND AML): Updated results from a phase 1 study.

Abstract

7028 Background: IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with mIDH1 relapsed or refractory AML. We report the safety and efficacy of IVO in pts with ND AML not eligible for standard therapy enrolled in the first-in-human, phase 1, dose escalation and expansion study of pts with mIDH1 advanced hematologic malignancies (NCT02074839). Methods: Enrollment completed on 08May2017. Overall response rate (ORR) comprised complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was CR except absolute neutrophil count > 0.5 × 109/L and platelet count > 50 × 109/L. Results: Baseline characteristics for 34 pts with ND AML who received IVO 500 mg once daily were: 19 men/15 women; median age 76.5 yrs (range 64-87); 56% ≥75 yrs of age; 76% had secondary AML and 53% prior MDS; 47% had ≥1 hypomethylating agent for an antecedent hematologic disorder. As of 02Nov2018, 7/34 (21%) pts remained on treatment; 3 (9%) had discontinued treatment for allogeneic stem cell transplant. Median duration of IVO exposure was 4.3 mo (range 0.3–40.9). Adverse events of any grade and causality in ≥25% of pts were diarrhea (53%), fatigue (47%), nausea (38%), decreased appetite (35%), leukocytosis, anemia, thrombocytopenia, peripheral edema (all 26%). Most were grade 1–2 and unrelated to treatment. IDH differentiation syndrome (DS) was seen in 6/34 (18%) pts, grade ≥3 in 3 (9%); IVO was held due to DS in 3 pts. QT prolongation was seen in 6 pts. In 33 pts confirmed mIDH1-positive by the companion diagnostic test, CR rate was 30% (95% CI 16%, 49%), CR+CRh 42% (95% CI 26%, 61%), and ORR 55% (95% CI 36%, 72%), with median durations not estimable (95% CI lower bound 4.2, 4.6, and 4.6 mo, respectively); 12-mo 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. Updated co-occurring mutation and mutation clearance data will be reported. Conclusions: IVO was well tolerated and induced durable remissions in elderly pts with poor-prognosis mIDH1 ND AML. Clinical trial information: NCT02074839.