Midostaurin Shows Rare Survival Improvement in FLT3-Mutated AML

Richard M. Stone, MD

Patients with FLT3-mutated acute myeloid leukemia (AML) lived significantly longer when treated with the multikinase inhibitor midostaurin (PKC412) compared with placebo, showed results of an international randomized trial reported at the 2015 ASH Annual Meeting.

Median overall survival (OS) with midostaurin was 74.7 versus 25.6 months in the placebo group. Event-free survival (EFS) was over twice as long with midostaurin, at 8.0 versus 3.6 months. Once censored for stem cell transplant, midostaurin continued to show an improvement in OS. The 4-year censored OS rate with midostaurin was 63.8% versus 55.7% for placebo (HR, 0.75; P = .04).

“On the basis of these results, midostaurin, added to chemotherapy, may be studied in older patients with AML. Because it is a multikinase inhibitor, midostaurin may be active in other subgroups of patients with AML and should be studied in those groups,” said Richard M. Stone, MD, director of the adult leukemia program at Dana-Farber Cancer Institute. “Overall survival and event-free survival benefit were consistent in uncensored as well as censored analyses, despite high stem cell transplant rates.”

In the prospective phase III trial, labeled CALGB 10603, 717 patients with newly diagnosed FLT3-mutant AML were randomized to standard chemotherapy plus midostaurin (n = 360) or placebo (n = 357). During induction, daunorubicin was given at 60 mg/m² on days 1 to 3 with cytarabine at 200 mg/m² on days 1 to 7 along with oral midostaurin at 50 mg twice daily on days 8 to 22.

If residual AML was detected on bone marrow exams, retreatment was allowed. Those who achieved a complete remission received 4 cycles of cytarabine at 3 g/m² every 12 hours on days 1, 3, and 5 plus midostaurin at 50 mg twice daily on days 8 to 22 followed by midostaurin maintenance at 50 mg twice daily.

The arms were well balanced for age, race, FLT3 subtype, and baseline complete blood counts. The median age of patients was 48 years. There were more males in the midostaurin arm versus placebo (48.2% vs 40.6%; P = .04).

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%). Twenty-five percent of transplant occurred during the first complete remission. Median time to transplant was similar in each arm at 4.5 to 5.0 months.

The primary endpoint was OS. Secondary endpoints included complete response rates, EFS, disease-free survival, and safety. Secondary analyses also looked at EFS and OS in those who received transplant.

At the median follow-up of 57 months, all patients were off active treatment. This analysis of the primary endpoint showed a statistically significant 23% reduction in the risk of death for patients treated with midostaurin (HR, 0.77, P =.0076). The 5-year OS rate for patients in the midostaurin arm was 50.9% versus 43.9% with placebo.

The difference in median EFS translated to a 21% reduction in hazard in favor of midostaurin, a difference that also achieved statistical significance (HR, 0.79, P = .0032). The 5-year EFS rate with midostaurin was 27.5% versus 19.3% with placebo. In those censored for transplant, the median EFS with midostaurin was also 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,” said Stone. “The safety profile was similar in each arm."

Originally developed as an inhibitor of VEGF and protein kinase C, midostaurin subsequently became recognized as an inhibitor of FLT3, which is mutated in about 35% of AML cases. In a preclinical model of FLT3-mutant AML, treatment with midostaurin was associated with prolonged survival, said Stone.

Laboratory and clinical studies have demonstrated that the drug has limited single-agent activity in advanced FLT3-mutant AML. However, other studies showed substantial activity in combination with conventional chemotherapy, and subsequent phase I-II clinical trials showed the targeted drug could be given safely with chemotherapy and resulted in encouraging activity. The first patient was enrolled in the phase III study in 2008.

"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," said Stone. "FLT3 is a common genetic mutation in AML and is currently associated with poorer prognoses, underscoring the critical need for new treatment options."

There are not currently any approved targeted therapies for patients with AML, representing a high unmet need. The current standard of care for patients is combination chemotherapy. Findings from the phase III study are being submitted to the FDA in the first half of 2016, according to the developer of midostaurin, Novartis.

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.

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