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Midostaurin the First Targeted Therapy to Improve Survival in AML: Potentially Practice-Changing

February 2016 Vol 9, Special Issue: Payers' Perspectives in Oncology - Emerging Therapies

The multikinase inhibitor midos­taurin is the first targeted therapy to improve overall survival (OS) in patients with acute myeloid leukemia (AML) and the FLT3 mutation. Midostaurin plus standard chemotherapy improved survival compared with placebo plus chemotherapy as an upfront 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 of the CALGB 10603/RATIFY trial were greeted with enthusiasm at ASH 2015. The study was an undertaking of the Alliance for Clinical Trials in Oncology.

At a median follow-up of 57 months, midostaurin reduced mortality risk by 23% compared with placebo plus chemotherapy. The median OS was 74.7 months for the group receiving midos­taurin versus 26 months for the placebo group (P = .007), representing a 23% reduction in the risk for death favoring midostaurin. “This represents a new standard of care for FLT3-mutated AML,” said Richard M. Stone, MD, Director, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston.

“These results…represent a long-­awaited advance for hematologists and the AML community,” Dr Stone told attendees. “This is the first step in applying the theories of personalized medicine to patients with AML, specifically those patients with AML who have a FLT3 mutation, who we have shown are likely to benefit from the addition of this targeted agent, midostaurin, to standard therapy.”

Approximately 30% of patients with AML carry the FLT3 mutation, which is associated with aggressive disease, with poor prognosis and a high risk for relapse. Among the FLT3 inhibitors under development, midostaurin is the first to demonstrate improved survival in patients with an FLT3 mutation in a phase 3 clinical trial.

RATIFY randomized 717 adults with AML and an FLT3 mutation to oral midostaurin or to placebo in addition to standard induction with daunorubicin plus cytarabine and consolidation chemotherapy (high-dose cytarabine). The patients who achieved a complete remission (CR) after consolidation chemotherapy continued treatment with single-agent midostaurin or with placebo as maintenance therapy for 1 year.

Midostaurin significantly improved event-free survival compared with placebo, with a median event-free survival of 8 months for midostaurin versus 3.6 months for placebo (P = .003), a 21% reduction in risk for events favoring midostaurin.

The patients were prestratified according to the 3 mutation subtypes of FLT3, including tyrosine kinase domain (TKD), internal tandem duplications (ITD) high, and ITD low. ITD FLT3 mutations carry a worse prognosis, and prognosis is less uncertain with TKD FLT3 mutations. Midostaurin improved OS and event-free survival in all 3 FLT3 subtypes versus placebo.

The patients who achieve a CR with midostaurin benefit from continued midostaurin therapy, with 25.9 months of disease-free survival with midostaurin versus 14 months with placebo in patients who achieved a CR.

Overall, 57% of the patients went on to undergo allogeneic stem-cell transplantation at first remission (28% in the midostaurin group and 22% in the placebo group); midostaurin achieved a survival benefit in patients who did and did not have a transplant.

Midostaurin had acceptable safety. No significant differences were observed in the overall rates of grade ≥3 hema­tologic and nonhematologic adverse events. A total of 37 deaths occurred, with no difference in treatment-related deaths 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. ECOG-ACRIN is now discussing the design of future trials,” said Mark R. Litzow, MD, Head of the Acute Leukemia Group, Mayo Clinic, Rochester, MN, regarding 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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Last modified: August 30, 2021