The FDA has granted priority review status to a new drug application for midostaurin (Novartis), an oral, multitargeted kinase inhibitor, for the treatment of newly diagnosed adults with acute myeloid leukemia (AML) with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of patients with advanced systemic mastocytosis (SM).
In addition, a premarket approval application for a midostaurin FLT3 companion diagnostic, developed by Novartis in collaboration with Invivoscribe Technologies, has been accepted for review by the FDA.
The NDA submission for midostaurin included data from the phase 3 RATIFY trial, which investigated midostaurin plus standard chemotherapy versus placebo plus standard chemotherapy in adults less than 60 years of age with FLT3-mutated AML. Those in the midostaurin arm experienced a statistically significant improvement in overall survival (OS), with a 23% reduction in the risk of death compared with the placebo arm (hazard ratio [HR], 0.77; P = 0.0074). Based on these data, midostaurin was also granted a breakthrough therapy designation by the FDA earlier this year for newly-diagnosed FLT3-mutated AML.
In the RATIFY trial, no statistically significant differences were observed in the overall rates of grade-3 or higher hematologic and nonhematologic adverse events in the midostaurin group compared with the placebo group. The most frequent adverse events (all grades) included febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae, and pyrexia.
Data from a phase-2 single-arm study of midostaurin in patients with advanced SM were published in the New England Journal of Medicine in June 2016. Treatment with midostaurin resulted in an overall response rate (defined as complete or partial resolution of organ damage) of 60%, with a median duration of response of 24.1 months. The most common adverse events were low-grade nausea, vomiting, and diarrhea.
AML is the most common acute leukemia in adults. Of the approximately 350,000 people with leukemias worldwide, approximately 25% have AML. AML has a low survival rate, with approximately 25% of patients surviving at five years.
SM consists of a group of rare diseases affecting between 1 in 20,000 to 1 in 40,000 people worldwide. The disease is characterized by the uncontrolled growth and accumulation of mast cells––mediators of allergic responses––in one or more organs. In advanced SM, mast cells accumulate in such large quantities that they begin to cause organ damage. Patients also experience debilitating systemic symptoms, such as pruritus, caused by mast cells releasing inflammatory mediators, such as histamine, into the blood. Median OS is currently between less than six months to 3.5 years, depending on the SM subtype.
Source: Novartis; November 14, 2016.