FDA Approval Sought for Ivosidenib in IDH1+ AML

Chris Bowden, MD

A new drug application (NDA) has been submitted for ivosidenib (AG-120) for patients with relapsed/refractory IDH1-mutant acute myeloid leukemia (AML), according to a statement from Agios Pharmaceuticals, the company developing the targeted therapy.

The NDA was based on findings from a phase I trial, which was presented at the 2017 ASH Annual Meeting. In the single-arm trial, patients treated with the dose of ivosidenib being submitted for approval (500 mg daily) had a complete response (CR) or CR with partial hematologic recovery (CRh) rate of 30.4%, which lasted for a median duration of 8.2 months. Of those in CR, 28% were negative for minimal residual disease (MRD).

Agios has requested a priority review from the FDA, under which the agency would render a decision within 6 months rather than 10 months for a standard review. The FDA will assign a review timeline within 60 days from the time of the NDA submission.

“People with AML who have relapsed or refractory disease have limited treatment options available to them, and it is our hope that we can change that,” Chris Bowden, MD, chief medical officer at Agios, said in a statement. “Earlier this month at the ASH Annual Meeting, we presented compelling single-agent ivosidenib data demonstrating durable responses in high-risk relapsed or refractory AML patients with an IDH1 mutation. These data highlight the potential for ivosidenib to be a first-in-class therapy for patients with R/R AML and an IDH1 mutation.”

In the phase I study, 78 patients with IDH1-mutant hematologic malignancies were enrolled in a dose escalation stage. Subsequently, a dose expansion cohort was opened for the 500-mg daily dose of ivosidenib, which enrolled 180 patients with IDH1-mutant hematologic malignancies across 4 groups of patients. The largest arm contained 126 patients with IDH1-mutant AML in their second relapse after stem cell transplant, those who were refractory to induction or reinduction therapy, or those relapsing within 1 year.

The primary analysis, which is being submitted to the FDA, was based on findings for 125 patients with relapsed/refractory AML who received 500 mg once daily of ivosidenib in the dose expansion (n = 92) and dose escalation cohort (n = 33). Patients had received a minimum of 6 months of treatment. Safety was assessed on all 258 patients enrolled in the trial in the dose escalation and dose expansion groups.

In the dose expansion group, 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.

In the combined analysis, the objective response rate (ORR) with ivosidenib was 41.6% with a 6.5-month median duration of response. In the dose expansion phase alone, 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.

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.

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%).

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.

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). Additionally, an expanded access program is currently available for those with relapsed/refractory AML with an IDH1 mutation (NCT03245424).

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.