Ivosidenib Shows High Single-Agent Activity for IDH1-mutant AML

Courtney D. DiNardo, MD

The IDH1 inhibitor ivosidenib (AG-120) induced a complete response (CR) or CR with partial hematologic recovery (CRh) for 30.4% of patients with relapsed/refractory IDH1-mutant acute myeloid leukemia (AML), according to phase I presented at the 2017 ASH Annual Meeting.

In the 125-patient analysis of those with relapsed/refractory AML, the objective response rate (ORR) with ivosidenib at 500 mg daily was 41.6% with a median duration of response of 6.5 months. The median duration of CR/CRh was 8.2 months. Of those in CR, 28% were negative for minimal residual disease (MRD).

All patients achieving a CR no longer required platelet transfusion and 84.6% were red blood cell (RBC)-transfusion independent. Across all patients in the trial, 39.1% and 39.7% of patients were independent of platelet and RBC transfusions, respectively. There was a decreased incidence of febrile neutropenia and infections in responders.

"In patients with relapsed/refractory AML, most of whom had received multiple prior AML treatments, ivosidenib induced durable responses," said lead investigator Courtney D. DiNardo, MD, from the University of Texas MD Anderson Cancer Center. "Patients with MRD-negative CR had improved overall survival compared to all other relapsed/refractory AML patients with persistent MRD."

In the single-arm phase I study, 78 patients with IDH1-mutant hematologic malignancies were enrolled in a dose escalation stage looking at 100 mg twice daily or doses ranging from 200 mg to 1200 mg once daily. Subsequently, a dose expansion cohort was opened and enrolled 180 patients for the 500-mg daily dose of ivosidenib.

The dose expansion cohort contained 4 arms. Arm 1 enrolled 126 patients in their second relapse after stem cell transplant, those who were refractory to induction or reinduction therapy, or those relapsing within 1 year with IDH1-mutant AML. Arm 2 enrolled 25 patients with untreated AML. Arm 3 enrolled 11 patients with other non-AML IDH1-mutant relapsed/refractory hematologic malignancies. A fourth arm included patients with relapsed/refractory IDH1-mutant AML who were not eligible for arm 1 (n = 18).

The primary relapsed/refractory AML analysis was conducted on 125 patients from the dose expansion (n = 92) and dose escalation cohort (n = 33) who received 500 mg once daily of ivosidenib. Patients had received a minimum of 6 months of treatment. Safety was assessed on all 258 patients enrolled in the trial.

In arm 1, the median age of patients was 67 years (range, 18-87) and 73% had an ECOG performance status of 0 or 1. The majority had de novo AML (66.4%) and the median number of prior therapies was 2 (range, 1-6). Most had intermediate (52.8%) or poor (30.4%) risk cytogenetics.

The CR rate was 21.6% and the CRh rate was 8.8%. The median time to CR/CRh was 2.7 months, and the median duration of CR was 9.3 months. Responses continued at 12 months for 32.4% and 41.2% of those experiencing CR/CRh and CR, respectively.

At the data cutoff in May 2017, 24% of patients continued to received treatment across the full study (9.6% in the relapsed/refractory AML analysis). The most common cause of discontinuation was disease progression, with 12.8% stopping treatment due to adverse events (AEs). The median treatment duration was 3.9 months in the AML analysis (range, 0.1-25.8).

The most common AEs regardless of cause were diarrhea (33.3%), leukocytosis (30.2%), nausea (29.5%), fatigue (28.7%), and febrile neutropenia (25.2%). The most common grade ≥3 AEs regardless of cause were febrile neutropenia (24.8%), anemia (19%), thrombocytopenia (13.6%), electrocardiogram QT prolongation (8.9%), and leukocytosis (6.6%).

"Grade 3 QT prolongation was reported in 10 of 125 patients. None were grade 4 or fatal. The study drug was reduced in 1 patient and held in 5 patients,” said DiNardo.

IDH-differentiation syndrome (IDH-DS) was reported in 9.6% of patients (n = 12), with one-third having co-occurring leukocytosis. These events were managed with corticosteroids and diuretics with hydroxyurea if accompanied by leukocytosis. None of the IDH-DS events were grade 4 or fatal. "These events were managed using standard of care treatments and ivosidenib dose modifications as required,” said DiNardo.

Promising responses to ivosidenib were also seen in an early assessment of those with untreated AML (n = 34) and myelodysplastic syndrome (MDS; n = 12). The ORR for untreated patients with AML was 55.9%, which included a CR rate of 20.6%. In those with MDS, the ORR was 91.7%. The CR rate was 41.7%.

Findings from the 125-patient primary AML analysis will be submitted to the FDA by the end of 2017, according to the company developing the medication, Agios Pharmaceuticals. The phase III AGILE trial is evaluating the combination of ivosidenib plus azacitidine compared with placebo and azacitidine for untreated patients with IDH1-mutant AML (NCT03173248).

DiNardo CD, De Botton S, Stein EM, et al. Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 725.

After 14.8 months of follow-up, the median overall survival (OS) was 8.8 months (95% CI, 6.7-10.2). The median OS was not yet reached in those achieving a CR/CRh and was 9.3 months for non-CR/CRh responders.