Midostaurin Granted Recommendation for EU Approval in AML

Bruno Strigini, CEO

Bruno Strigini, CEO

Midostaurin (Rydapt) has been recommended for approval by the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) to treat adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation—positive.

The CHMP also issued a positive opinion on midostaurin monotherapy for adults with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia.

In the phase III RATIFY trial, midostaurin reduced the risk of death by 23% when added to daunorubicin and cytarabine induction and high-dose cytarabine consolidation versus chemotherapy alone in patients with FLT3-positive AML. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained steady at 25%.

If approved, midostaurin would be the first targeted treatment available in the European Union (EU) for these patient populations.

"Novartis is dedicated to bringing new treatment options to patients with rare diseases, including AML and advanced SM, which have seen limited treatment developments in the past 25 years," Bruno Strigini, CEO, Novartis Oncology, the manufacturer of midostaurin, said in a statement. "We are pleased with the positive recommendation from the CHMP and excited to move a step closer to bringing this much-needed treatment to these patients across Europe."

In the 2 single-arm, open-label studies (including the phase II CPKC412D2201 trial) considered for the SM indications, the overall response rate (modified Valent criteria) with midostaurin was 59.6% (95% CI, 48.6-69.8).

In the phase III RATIFY trial, also known as CALGB 10603, 717 patients with newly diagnosed FLT3-mutant AML were randomly assigned 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, researchers administered 60 mg/m2 daunorubicin on days 1 to 3 along with 200 mg/m2 cytarabine on days 1 to 7. Midostaurin was administered at 50 mg twice daily on days 8 to 22.

Patients who achieved complete remission received 3 g/m2 cytarabine as consolidation therapy for 3 hours every 12 hours on days 1, 3, and 5 plus either placebo or midostaurin. After 4 cycles of consolidation, patients received up to 1 year of 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; 95% CI, 0.63-0.95;P= .0078). 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 versus 3.0 months with placebo (HR, 0.78; 95% CI, 0.66-0.93;P= .0024). 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, which could be due to 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).

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).