The new drug application (NDA) was based on findings from a phase I trial that was presented at the 2017 ASH Annual Meeting. In the single-arm trial, patients treated with the FDA-submitted 500 mg daily dose of ivosidenib 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).
The FDA will decide on the application for the oral inhibitor of mutant IDH1 ivosidenib by August 21, 2018, as part of the Prescription Drug User Fee Act (PDUFA).
“After decades of little change, treatment of AML has begun to shift dramatically as result of new therapies, and IDH mutation inhibitors will play an important role in how we treat this terrible disease,” David Schenkein, MD, chief executive officer of Agios, said in a statement. “Today marks an important milestone in our efforts to rapidly advance what could be the first targeted treatment for relapsed/refractory AML patients with an IDH1 mutation. We appreciate the FDA’s collaboration during the application process, and we look forward to continuing our productive dialogue.”
In addition to the NDA, a premarket approval application was also submitted to the FDA for a companion diagnostic to detect IDH1 mutations, which occur in 6% to 10% of patients with AML. The assay, Abbott's m2000 RealTime System, automatically prepares samples and analyzes batches for nucleic acid amplification and detection.
The phase I study that was the basis for the NDA initially enrolled 78 patients with IDH1-mutant hematologic malignancies. 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 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).