February 2016, Vol. 5, No. 1
Midostaurin: First Targeted Therapy in AML Is Potentially Practice Changing
Midostaurin is the first FLT3 inhibitor to improve overall survival in FLT3-mutated acute myeloid leukemia (AML). Midostaurin plus standard chemotherapy improved survival compared with placebo plus chemotherapy as up-front treatment for high-risk patients with AML and FLT3 mutations.
Patients and physicians have waited for new drugs for AML since the 1990s, so the results from the CALGB 10603/RATIFY trial were greeted with enthusiasm. The study was an undertaking of the Alliance for Clinical Trials in Oncology.
At a median follow-up of 57 months, midostaurin reduced the risk of death by 23% compared with placebo plus chemotherapy. Median overall survival was 74.7 months for the midostaurin-treated group versus 26 months for the placebo group (P = .007).
“This represents a new standard of care for FLT3-mutated AML,” said Richard M. Stone, MD, Director, Adult Acute Leukemia Program, Dana-Farber Cancer Institute, Boston, MA.
“These results…represent a long-awaited advance for hematologists and the AML community. This is the first step in applying the theories of personalized medicine to patients with AML, specifically those patients with AML who have an FLT3 mutation, who we have shown are likely to benefit from the addition of this targeted agent, midostaurin, to standard therapy,” he told listeners.
About 30% of patients with AML carry the FLT3 mutation, which is associated with aggressive disease with poor prognosis and high risk of relapse. Among the FLT3 inhibitors under development, midostaurin is the first to demonstrate improved survival in patients with FLT3 mutations in a phase 3 trial.
In the RATIFY trial, 717 adults with FLT3-mutated AML were randomized to receive oral midostaurin or placebo in addition to standard induction (daunorubicin/cytarabine) and consolidation chemotherapy (high-dose cytarabine). Patients who achieved a complete remission (CR) after consolidation chemotherapy continued treatment with single-agent midostaurin or placebo for 1 year of maintenance therapy.
Midostaurin significantly improved event-free survival (EFS) compared with placebo: median EFS was 8 months for midostaurin versus 3.6 months for placebo (P = .0032), representing a 21% reduction in risk of events favoring midostaurin.
Patients were prestratified according to 3 mutation subtypes: tyrosine kinase domain (TKD), internal tandem duplications (ITDs) high, and ITDs low. ITD mutations carry a worse prognosis, and prognosis is less certain with TKD mutations. Midostaurin improved overall survival as well as EFS in all 3 FLT3 subtypes versus placebo.
Patients who achieve a CR on midostaurin benefit from continued midostaurin: disease-free survival was 25.9 months for midostaurin and 14 months for placebo.
More than half of the patients (57%) went on to undergo allogeneic stem cell transplantation at first remission (28% in the midostaurin group and 22% in the placebo group); treatment with midostaurin resulted in a survival benefit in transplant and nontransplant patients.
Midostaurin had acceptable safety. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and nonhematologic adverse events. A total of 37 deaths occurred, with no difference in treatment-related deaths seen between the 2 groups.
“The study does have the potential to be practice changing, and midostaurin should be considered as part of the control arm of future studies. The Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network are now discussing the design of future trials,” said Mark Litzow, MD, Mayo Clinic, Rochester, MN, commenting on the RATIFY trial. “But it may turn out that other drugs out there prove to be better FLT3 inhibitors,” he added.
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