NDA Submitted for Ivosidenib for Relapsed/Refractory IDH1-Positive AML

The FDA received a new drug application (NDA) for ivosidenib (previously AG-120) for patients with relapsed/refractory IDH1-positive acute myeloid leukemia (AML).

The NDA was based on findings from an ongoing, single-arm, phase I trial, which was presented at the 2017 ASH Annual Meeting. A total of 258 patients (78 in the dose-escalation phase and 180 in the dose-expansion phase) were treated with ivosidenib. As of May 12, 2017 (data cutoff), 24 percent of patients (n=62) were continuing treatment, and the median duration of exposure was 3.5 months (range = 0.1-33.5 months). Twenty-two patients (8.5%) discontinued treatment and went on to receive allogeneic hematopoietic cell transplantation.

The most common any-grade AEs (occurring in ≥20% of patients) were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). Twenty-nine participants (11.2%) reported differentiation syndrome (DS), 14 (5.4%) of which were grade ≥3. Treatment was held because of DS in 11 patients (4.3%), but no instances led to permanent treatment discontinuation or death. The most common cause of treatment discontinuation was disease progression, with 12.8 percent stopping treatment because of AEs.

Among 125 patients with relapsed/refractory AML who received ivosidenib 500 mg for a minimum of six months (92 in dose-expansion and 33 in dose-escalation phases), the rate of complete response (CR) or CR with partial hematologic recovery (CRh; primary endpoint) was 30.4 percent, which lasted for a median duration of 8.2 months (95% CI 5.5-12.0; range not provided). The median duration of response was 6.5 months (range not provided). Of those who achieved CR, 28 percent were minimal residual disease–negative.

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 reached in those achieving a CR/CRh and was 9.3 months for non-responders.

Sources: Agios press release, December 26, 2017; 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. Abstract #725. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.