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The FDA granted Priority Review to the midostaurin (PKC412) NDA for the treatment of acute myeloid leukemia (AML) in newly diagnosed adults with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of advanced systemic mastocytosis (SM).

FDA; Midostaurin. FD... - Click to enlarge in new windowFDA; Midostaurin. FDA; Midostaurin

The NDA submission for midostaurin includes data from the largest clinical trials conducted to date in each indication. In the phase III RATIFY trial (CALGB 10603), which investigated midostaurin plus standard chemotherapy versus placebo plus standard chemotherapy in adult patients less than 60 years of age with FLT3-mutated AML, those in the midostaurin arm experienced a statistically significant improvement in overall survival with a 23 percent reduction in risk of death compared to the placebo arm (hazard ratio [HR] = 0.77, P = 0.0074). Based on these data, midostaurin also was granted 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 rate of grade 3 or higher hematologic and non-hematologic adverse events (AEs) in the midostaurin treatment group versus the placebo group. The most frequent all grade AEs were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae, and pyrexia. A total of 36 deaths occurring within 30 days of the last dose of study drug were reported, with no difference in treatment-related deaths observed between groups.


Data from the phase II single-arm study (CPKC412D2201) evaluating the efficacy of midostaurin in patients with advanced SM were published in the New England Journal of Medicine in June 2016. The study showed treatment with midostaurin resulted in an overall response rate of 60 percent with a median duration of response of 24.1 months (95% CI, 10.8-not estimated [NE]) and a median OS of 28.7 months (95% CI, 18.1-NE). The most frequent AEs were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred mostly in patients with pre-existing cytopenias.