FDA Approves Rydapt (midostaurin) for Rare Blood Cancers

James Radke

The FDA has approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy.  
The drug is approved in combination with the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

The FDA also approved midostaurin to treat adults with certain types of rare blood disorders (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm or mast cell leukemia).

AML and Rydapt (midostaurin)

Acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes abnormal myeloblasts. Symptoms include fatigue, recurrent infections and easy bruising. Acute myeloid leukemia is generally a disease of older people and is uncommon before the age of 45. The National Cancer Institute estimated that approximately 19,930 people would be diagnosed with AML in 2016 and 10,430 expected to die of the disease.

Mutations in specific genes are found in many cases of AML, and biomarker testing is considered standard of care for newly-diagnosed patients to help determine the best possible treatment option. FLT3 is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells. Rydapt is a kinase inhibitor that works by blocking several enzymes that promote cell growth.
AML is typically treated with chemotherapy and the intensity of chemotherapy depends on a person's age and health.

“Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment.”

The approval is based on the phase III RATIFY trial in which 717 patients with newly diagnosed FLT3-mutant AML were randomized to standard induction and consolidation chemotherapy plus midostaurin (n = 360) or placebo (n = 357).
The trial found that the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone in patients with AML who had the FLT3 mutation.
Median overall survival (OS) was 74.7 months with midostaurin versus 25.6 months with chemotherapy alone (HR, 0.77; 95% CI, 0.63-0.95; P = .016). The 5-year OS rate for patients in the midostaurin arm was 50.9% versus 43.9% with placebo. Median event free survival (EFS) in the midostaurin arm was 8.2 compared to 3.0 months with placebo (HR, 0.78; 95% CI, 0.66-0.93; P = .004). The 5-year EFS rate with midostaurin was 27.5% versus 19.3% with placebo.

The most frequent adverse reactions (incidence greater than or equal to 20%) in the midostaurin plus chemotherapy arm were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae (small red skin spots), device-related infection, epistaxis, hyperglycemia and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis.

Systemic Mastocytosis and Rydapt (Midostaurin)

In the phase II trial considered for the approving midostaurin to treat patients with systemic mastocytosis, patients received 6 cycles of midostaurin and the rates of complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria were 38% for aggressive systemic mastocycytosis and 16% for systemic mastocytosis with associated hematological neoplasm.

Advanced systemic mastocytosis is a rare blood disorder characterized by uncontrolled growth and accumulation of mast cells in 1 or more organs. Median overall survival is currently less than six months for mast cell leukemia, two years for systemic mastocytosis with associated hematological neoplasm.and 3.5 years for aggressive systemic mastocytosis.
The approval of midostaurin was based on two single-arm open-label multicenter trials. The efficacy of midostaurin was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of treatment. This analysis demonstrated an overall response rate of 21% (95% CI, 13, 31).

The most frequent adverse reactions (incidence greater than or equal to 20%), excluding laboratory terms, 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 greater adverse reactions (incidence greater than or equal to 5%), excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain and renal insufficiency.
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