Midostaurin Granted an FDA Priority Review for AML

Midostaurin (PKC412) was granted a priority review to a new drug application (NDA) to treat 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 3 RATIFY trial in AML and a single-arm phase 2 study of patients with SM. In the RATIFY trial, the addition of midostaurin to standard chemotherapy reduced the risk of death by 23 percent 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 percent.

The phase 2 data submitted for midostaurin in SM showed that the drug had an overall response rate of 60 percent 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 six 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 3 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 (360 patients) or placebo (357 patients). Hydroxyurea was allowed for up to five days prior to beginning therapy, while FLT3 test results were obtained.

During induction therapy, daunorubicin was given at 60 mg/m² on days one to three with cytarabine at 200 mg/m² on days one to seven. Oral midostaurin was administered at 50 mg twice daily on days eight to 22. If patients achieved a complete remission, consolidation therapy was given with cytarabine at 3 g/m² for three hours every 12 hours on days one, three and five plus either placebo or midostaurin. After four cycles of consolidation, maintenance therapy with either midostaurin or placebo was administered for up to one 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 percent vs 40.6 percent). 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. The five-year OS rate for patients in the midostaurin arm was 50.9 percent versus 43.9 percent with placebo. Median EFS in the midostaurin arm was 8.0 versus 3.6 months with placebo. The five-year EFS rate with midostaurin was 27.5 percent versus 19.3 percent 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.

Overall, 57 percent of patients received an allogeneic stem cell transplant at any time during the trial, more commonly in the midostaurin arm versus placebo (58 percent vs 54 percent). 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 percent of patients in the midostaurin arm and 54 percent in the placebo group experienced a complete remission.

Median OS data were not obtained in the censored population. Overall, the 4-year censored OS rate with midostaurin was 63.8 percent versus 55.7 percent for placebo. In those censored for transplant, median EFS with midostaurin was 8.2 versus 3.0 months with placebo.

Grade 3 or higher AEs were similar between the midostaurin and placebo arms. Overall, 37 grade 5 AEs occurred in the study, which were similar between the two arms, at 5.3 percent with midostaurin versus 5.0 percent with placebo. A statistically significant difference was not observed for treatment-related grade 5 AEs.

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.