Midostaurin Granted Priority Review for AML, Systemic Mastocytosis

The FDA has granted a priority review to the multikinase inhibitor midostaurin as a treatment for patients with newly-diagnosed&nbsp;<em>FLT3</em>-mutated acute myeloid leukemia or advanced systemic mastocytosis.

FLT3-mutated acute myeloid leukemia (AML) or advanced systemic mastocytosis (SM), according to a statement from Novartis, the developer of the drug.

The application for midostaurin is based on data from the phase III RATIFY trial in AML1and a single-arm phase II study of patients with SM.2The phase II data submitted for midostaurin in SM showed that the drug had an overall response rate of 60% and a median duration of response of 24.1 months. The median OS was 28.7 months.&nbsp;In the RATIFY trial, the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone in patients with AML who harbored an&nbsp;FLT3mutation. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained steady at 25%.

​According to Novartis, approximately one-third of patients with AML harborFLT3mutations, which are linked to more aggressive disease, with a higher risk of relapse and shorter survival duration. Along with the NDA for midostaurin, the FDA also accepted a premarket approval application for an&nbsp;FLT3companion diagnostic that Novartis developed in collaboration with Invivoscribe Technologies.

The priority review follows an FDA breakthrough therapy designation granted to midostaurin in February 2016 for newly diagnosed patients withFLT3-mutated AML. Under the expedited designation, the NDA will be reviewed within 6 months, compared with the standard 10-month review.

&ldquo;FLT3-mutated AML and advanced SM are devastating and rare diseases, with significant unmet needs due to limited existing treatment options,&rdquo; Bruno Strigini, CEO, Novartis Oncology, said in a press release. &ldquo;This regulatory designation signifies the importance of midostaurin as a potential therapy for these patients who haven&rsquo;t had the benefit of targeted medicines.&rdquo;

In the phase III RATIFY trial, also known as CALGB 10603, 717 patients with newly diagnosedFLT3-mutant AML were randomized to standard induction and consolidation chemotherapy plus midostaurin (n = 360) or placebo (n = 357). Hydroxyurea was allowed for up to 5 days prior to beginning therapy, whileFLT3test results were obtained.

During induction therapy, daunorubicin was given at 60 mg/m2on days 1 to 3 with cytarabine at 200 mg/m2on days 1 to 7. Oral midostaurin was administered at 50 mg twice daily on days 8 to 22. If patients achieved a complete remission, consolidation therapy was given with cytarabine at 3 g/m2for 3 hours every 12 hours on days 1, 3, and 5 plus either placebo or midostaurin. After 4 cycles of consolidation, maintenance therapy with either midostaurin or placebo was administered for up to 1 year.

The 2 treatment arms were well balanced for age (median, 48 years), race,FLT3subtype, and baseline complete blood counts. There were more males in the midostaurin arm versus placebo (48.2% vs 40.6%). The primary endpoint of the study was OS, with secondary outcome measures such as event-free survival (EFS) and safety.

In uncensored data, median OS was 74.7 months with midostaurin versus 25.6 months with chemotherapy alone (HR, 0.77;P= .0074). The 5-year OS rate for patients in the midostaurin arm was 50.9% versus 43.9% with placebo. Median EFS in the midostaurin arm was 8.0 versus 3.6 months with placebo (HR, 0.79;&nbsp;P= .0032). The 5-year EFS rate with midostaurin was 27.5% versus 19.3% with placebo.

Median OS seen in the midostaurin arm was well beyond investigator expectations of 20.9 months. A possible explanation for this could be the rates of stem cell transplantation or incomplete data. The confidence intervals for OS were not fully attained for the midostaurin arm (95% CI, 31.7 - not attained).

Overall, 57% of patients received an allogeneic stem cell transplant at any time during the trial, more commonly in the midostaurin arm versus placebo (58% vs 54%). Median time to transplant was 5.0 months with midostaurin and 4.5 months with placebo. Twenty-five percent of transplants occurred during the first complete remission. Overall, 59% of patients in the midostaurin arm and 54% in the placebo group experienced a complete remission (P= .18).

Median OS data were not obtained in the censored population. Overall, the 4-year censored OS rate with midostaurin was 63.8% versus 55.7% for placebo (HR, 0.75;P= .04). In those censored for transplant, median EFS with midostaurin was 8.2 versus 3.0 months with placebo (HR, 0.84;&nbsp;P= .025).

Grade &ge;3 AEs were similar between the midostaurin and placebo arms. Overall, 37 grade 5 AEs occurred in the study, which were similar between the 2 arms, at 5.3% with midostaurin versus 5.0% with placebo. A statistically significant difference was not observed for treatment-related grade 5 AEs (P= .82).

In Europe, the EMA previously accepted a marketing authorization application for midostaurin for use in newly diagnosedFLT3-positive AML and SM.


Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 6.

Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis.N Engl J Med. 2016;374(26):2530-2541.

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