Ivosidenib Monotherapy in Patients with Relapsed/Refractory AML and Other Advanced Hematologic Malignancies

Conference Correspondent - ASH 2017


An ongoing, first-in-human phase 1 study evaluated the safety and efficacy of single-agent ivosidenib (AG-120), an oral selective small-molecule inhibitor of mutant IDH1 (mIDH1) protein, in 258 patients with mIDH1-positive advanced hematologic malignancies including relapsed/refractory (R/R) acute myeloid leukemia (AML); this is the first report of data from the 4 expansion cohorts.

In the dose-escalation phase, 78 patients received oral ivosidenib monotherapy (100 mg-1200 mg) once daily or twice daily in continuous 28-day cycles; the maximum tolerated dose was not reached. The dose of 500 mg once daily was selected as that recommended to be tested in 4 expansion cohorts: arm 1 included 126 patients with relapse after transplantation, second or later relapse, refractory to initial induction or reinduction treatment, or relapse within 1 year of initial treatment; arm 2 included 25 patients with untreated AML not eligible for standard of care; arm 3 included 11 patients with other non-AML mIDH1 R/R advanced hematologic malignancies; and arm 4 included 18 poor-prognosis patients with R/R AML who were not eligible to be enrolled in arm 1. The efficacy analysis data set included 125 patients treated in the dose-escalation (500 mg once daily; n = 33) and arm 1 expansion cohort (n = 92) who received their first dose of ivosidenib at least 6 months prior to the analysis cutoff date of May 12, 2017. The safety analysis set included all 258 patients enrolled in the dose-escalation and expansion phases. For the R/R AML patient cohort, the primary efficacy end point is the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh), per the modified International Working Group 2003 criteria.

At the analysis cutoff, 78 of the 258 patients enrolled in the study in the dose-escalation phase and 180 patients in the expansion cohort had received ivosidenib therapy; 62 (24%) patients were continuing treatment and 22 (8.5%) discontinued treatment to proceed to allogeneic stem-cell transplantation. The median duration of exposure to ivosidenib in the primary R/R AML set was 3.9 months (range, 0.1-25.5 months). The median age of the R/R AML analysis set (n = 125) was 67, and the median number of prior therapies was 2 (range, 1-6); 42 (34%) patients had secondary AML, 10 patients had FLT3 co-mutations. In terms of cytogenetic risk, 66 (53%) patients were classified as intermediate risk, and 38 patients as poor risk.

The majority of adverse events (AEs) reported on the trial were grades 1 and 2, and were deemed unrelated to treatment. The most common AEs (n = 258; any grade or causality) occurring in ≥15% of patients were diarrhea (33%), leukocytosis (30%), nausea (29.5%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (22.5%), peripheral edema (22%), pyrexia (20.5%), and decreased appetite (20%). Notably, 12 (10%) patients experienced any grade differentiation syndrome and 4, co-occurring leukocytosis (none grade 4 or 5); however, these did not lead to permanent treatment discontinuation or death. IDH-inhibitor–associated differentiation syndrome was managed with corticosteroids and diuretics, and with hydroxyurea if accompanied by leukocytosis. In terms of ECG QT prolongation, grade 3 prolongation was reported in 10/125 (8%) patients (none were grade 4 or fatal); it was managed by dose reduction (n = 1) and withholding the drug in 5 patients.

In the R/R AML cohort (n = 125), the CR+CRh rate was 30.4% (95% confidence interval [CI], 22.5%-39.3%), including 27 (21.6%) CRs and 11 (8.8%) CRhs (CR with incomplete hematologic recovery/CR with incomplete platelet recovery, 6; morphologic leukemia-free state, 5). The median duration of CR+CRh was 8.2 months (95% CI, 5.5-12.0), and duration of CR was 9.3 months (95% CI, 5.6-18.3). Median time to CR+CRh was 2.7 months (range, 0.9-5.6 months), and time to CR was 2.8 months (range, 0.9-5.6 months). The overall response rate was 41.6% (95% CI, 32.9%-50.8%).

Based on the results of this large cohort of patients with mIDH1 AML and other advanced hematologic malignancies, it was concluded that ivosidenib monotherapy is well-tolerated and yielded durable remission.

DiNardo CD, et al. 2017 ASH. Abstract 725.