Pivotal Midostaurin Study in AML Patients Published in NEJM

James Radke

The data that led to the April FDA approval of Rydapt (midostaurin) to treat patients with acute myeloid leukemia (AML) who have an fms-related tyrosine kinase 3 gene (FLT3) mutation was published in the New England Journal of Medicine today.
AML is a rare cancer in which bone marrow produces abnormal myeloblasts. According to the National Cancer Institute, approximately 19,000 people will be diagnosed this year with AML and more than 10,000 will die.
Gene mutations are present in many AML patients and approximately 30% of newly diagnosed patients have an FLT3 mutation. The FLT3 gene creates FLT3, a receptor tyrosine kinase that plays a role in cell proliferation and growth. Midostaurin is a kinase inhibitor that can block enzymes involved in promoting cell growth.
In the phase 3 study by Dr.  Richard Stone and colleagues, 717 patients were randomized to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo. The groups were stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively. 
The primary end point was overall survival.
The study observed that overall survival was significantly longer in the midostaurin group (74.7 months) compared to the placebo group (25.6 months; P = .009). The 4-year overall survival rate was 51.4% in the midostaurin group and 44.3% in the placebo group. Median event-free survival was 8.2 months in the midostaurin group vs 3.0 months in the placebo group (P = .002).
The study also noted that midostaurin’s superiority regarding overall survival and event free survival were observed in all FLT3 subtypes. 
The most frequent Grade 3 to 5 non-hematologic adverse events in the midostaurin group were febrile neutropenia and infection. In the placebo arm, the most common adverse effects (AEs) were febrile neutropenia, infection and lymphopenia.
In their discussion, the authors theorized that “Since exposure to the FLT3 inhibitor was relatively brief (median duration of trial treatment, 3 months), it is probable that the major effect of the inhibitor was the early reduction of disease burden, although other potential explanations are possible.” 

Stone RM,  Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. New Engl J Med. Published online ahead of print, June 23, 2017. DOI: 10.1056/NEJMoa1614359
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