FDA Approves Midostaurin and a Companion Diagnostic

Midostaurin is approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive

On 28 April, 2017, the US Food and Drug Administration (FDA) approved midostaurin (RYDAPT, Novartis Pharmaceuticals Corp.) for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

The FDA also approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies Inc.), for use with midostaurin to test patients with AML for the FLT3 mutation.

Approval was based on a randomised, double-blind, placebo-controlled trial in 717 patients with previously untreated FLT3+ AML. This trial randomised patients to either placebo or midostaurin 50 mg orally twice daily on days 8-21 of each cycle of induction and consolidation chemotherapy followed by continuous daily midostaurin for up to 12 cycles.

The trial demonstrated a statistically significant improvement in overall survival (OS) for patients receiving midostaurin compared with those on the placebo-containing arm (HR 0.77, p=0.016).

Common adverse reactions, occurring in at least 20% of patients, included febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycaemia, and upper respiratory tract infection. The most frequent serious adverse reaction was febrile neutropenia, occurring in 16% of patients on both arms.

The FDA also approved midostaurin for the treatment of adults with aggressive systemic mastocytosis (SM), SM with associated haematological neoplasm, or mast cell leukaemia. 

Approval was based on response rate and duration in a single-arm, open-label study of midostaurin 100 mg orally twice daily. With 6 cycles of midostaurin, the rates of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria were 38% for ASM and 16% for SM-AHN. One patient (5%) with mast cell leukaemia achieved a CR.

The most common adverse reactions included nausea, vomiting, diarrhoea, oedema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, fever, headache, and dyspnoea.

The recommended dose of midostaurin in AML is 50 mg twice daily with food on days 8 to 21 of each cycle of induction and consolidation chemotherapy followed by 50 mg with food as a single agent for up to 12 months.

The recommended dose for the treatment of adults with aggressive SM, SM with associated haematological neoplasm, or mast cell leukaemia is 100 mg twice daily with food.

Full prescribing information is available here.  

The FDA granted this application Breakthrough Therapy Designation in AML, Fast Track Designation in SM, and priority review.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.