FDA Designates Midostaurin as a Breakthrough Therapy for Adults With AML

The FDA has handed down a breakthrough therapy designation for midostaurin (PKC412) as a potential treatment for adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML).

In the phase III RATIFY (CALGB 10603) trial, the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained steady at 25%. Novartis plans to submit data from the study to the FDA within the first half of 2016.

The trial was the designation for the FDA's decision.

“For more than 25 years, medical developments have been limited for AML patients and the chemotherapy treatment strategy has essentially remained unchanged,” Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs, said in a statement. "We look forward to working closely with the FDA to bring PKC412 (midostaurin), the first potential AML targeted therapy, to patients as quickly as possible.”

In the trial, 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 3g/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 two 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%;P= .04). 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).

Grade ≥3 adverse events (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% with midostaurin versus 5.0% with placebo. A statistically significant difference was not observed for treatment-related grade 5 AEs (P= .82).

“Overall survival and event-free survival benefit was consistent in uncensored as well as censored analyses, despite high stem cell transplant rates,” lead investigator Richard M. Stone, MD, director of the adult leukemia program at Dana-Farber Cancer Institute, said when he presented at the data at the 2015 ASH Annual Meeting.

“The overall survival results for midostaurin, plus standard chemotherapy, in treating FLT3-mutated AML is a long-awaited advancement for hematologists and the AML community.”