The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).

If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.

Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.

Midostaurin in AML

The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

CHMP recommends midostaurin for FLT3+ AML, SM