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.
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).
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).
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.
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.