FDA Grants Midostaurin Priority Review for AML

Bruno Strigini, CEO

The FDA granted a priority review to a new drug application (NDA) for midostaurin (PKC412) for adult patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) or advanced systemic mastocytosis (SM), according to a statement from Novartis, the developer of the multikinase inhibitor.

The NDA is based on the phase III RATIFY trial in AML¹ and a single-arm phase II study of patients with SM.² 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 FLT3 mutation. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained steady at 25%.

The 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. Low-grade nausea, vomiting, and diarrhea were the most common adverse events (AEs). Grade 3/4 neutropenia, anemia, and thrombocytopenia were mostly reported in patients who had pre-existing cytopenias.

The priority review follows an FDA breakthrough therapy designation granted to midostaurin in February 2016 for newly diagnosed patients with FLT3-mutated AML. Under the expedited designation, the NDA will be reviewed within 6 months, compared with the standard 10-month review.

“FLT3-mutated AML and advanced SM are devastating and rare diseases, with significant unmet needs due to limited existing treatment options,” Bruno Strigini, CEO, Novartis Oncology, said in a press release. “This regulatory designation signifies the importance of midostaurin as a potential therapy for these patients who haven’t had the benefit of targeted medicines.”

In the phase III RATIFY trial, also known as CALGB 10603, 717 patients with newly diagnosed FLT3-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, while FLT3 test results were obtained.

During induction therapy, daunorubicin was given at 60 mg/m² on days 1 to 3 with cytarabine at 200 mg/m² on 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/m² for 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, FLT3 subtype, 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; 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; P = .025).

According to Novartis, approximately one-third of patients with AML harbor FLT3 mutations, 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 FLT3 companion diagnostic that Novartis developed in collaboration with Invivoscribe Technologies.

In Europe, the EMA previously accepted a marketing authorization application for midostaurin for use in newly diagnosed FLT3-positive AML and SM.

References

1. 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.
2. 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.

Grade ≥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).