The U.S. Food and Drug Administration (FDA) granted priority review to midostaurin for adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) or advanced systemic mastocytosis (SM).
The decision was based on the results of the phase II RATIFY trial of patients with AML and a single-arm, open-label, phase II study of patients with SM.
In the RATIFY trial, 717 patients were randomized to receive standard “7+3” induction and consolidation chemotherapy with daunorubicin and cytarabine, plus oral midostaurin 50 mg (n=360) or placebo (n=357). After four cycles of consolidation, maintenance therapy with either midostaurin or placebo was administered for up to one year. The addition of midostaurin to standard chemotherapy reduced the risk of death by 23 percent compared with chemotherapy alone: overall survival (OS; primary endpoint) was 74.7 months with midostaurin versus 25.6 months with chemotherapy alone (hazard ratio [HR] = 0.77; p=0.0074). The five-year OS rate for patients in the midostaurin group was 50.9 percent compared with 43.9 percent receiving placebo. Grade ≥3 adverse events (AEs) were similar between the treatment cohorts.
In the SM trial, 116 patients received midostaurin 100 mg twice daily. The overall response rate (ORR) was 60 percent (95% CI 49-70); 45 percent of patients had a major response (defined as a complete resolution of at least one type of mastocytosis-related organ damage). The median OS was 28.7 months, and the median progression-free survival (PFS) was 14.1 months. AE-related dose reductions occurred in 56 percent of the patients. Nausea, vomiting, and diarrhea were the most common treatment-related AEs. Grade 3/4 neutropenia, anemia, and thrombocytopenia were also reported.
Sources: Novartis press release, November 14, 2016; Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530-41.