ON APRIL 28, 2017, midostaurin (Rydapt) was approved for treatment of adults with newly diagnosed acute myeloid leukemia (AML) who have FLT3 mutation–positive disease, as detected by a U.S. Food and Drug Administration (FDA)-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.^1,2 The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay to test for the FLT3 mutation. The FDA also approved midostaurin for the treatment of adults with aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm (systemic mastocytosis-associated hematologic neoplasm), or mast cell leukemia (collectively, systemic mastocytosis).^1,2 

Supporting Efficacy Data 

APPROVAL IN FTL3-POSITIVE AML was based on improved overall survival in a phase III double-blind trial in which 717 patients were randomized to receive oral midostaurin at 50 mg twice daily (n = 360) or placebo (n = 357) on days 8 to 21 of each 28-day cycle of standard daunorubicin-cytarabine induction (up to 2 cycles) and cytarabine consolidation (up to 4 cycles) followed by continuous daily midostaurin or placebo for up to 12 cycles. 

Patients had a median age of 47 years, 56% were female (52% in the midostaurin group vs 59% in the placebo group), 88% had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 95% had de novo AML. The percentage of patients with FLT3-internal tandem duplication allelic ratio < 0.7, FLT3-internal tandem duplication allelic ratio ≥ 0.7, and FLT3-tyrosine kinase domain mutations were 48%, 30%, and 23% in each group, respectively. 

After a minimum follow-up of approximately 3.5 years after randomization of the last patient, midostaurin plus standard chemotherapy was superior to placebo plus standard chemotherapy in terms of overall survival (hazard ratio [HR] = 0.77, P = .016). Median survival was not reached in either group. Median event-free survival was 8.2 months vs 3.0 months (HR = 0.78, P = .005). 

The approval in systemic mastocytosis was based on durable responses in a single-arm study in which 89 evaluable patients with aggressive systemic mastocytosis (n = 16), systemic mastocytosis-associated hematologic neoplasm (n = 57), or mast cell leukemia (n = 16) received midostaurin at 100 mg twice daily in 28-day cycles. The rates of confirmed complete remission plus incomplete remission by 6 cycles of treatment on modified Valent criteria were 21% overall, 38% in aggressive systemic mastocytosis, 16% in systemic mastocytosis-associated hematologic neoplasm, and 25% in mast cell leukemia. Median durations of response were not reached overall or in any subgroup, with responses ranging from 6.6+ to 65.8+ months. 

How It Works 

MIDOSTAURIN IS a small-molecule inhibitor of multiple receptor tyrosine kinases, with the parent compound or its major active metabolites (CGP62221 and CGP52421) inhibiting the activity of wild-type FLT3, FLT3-mutant kinases (internal tandem duplication and tyrosine kinase domain), KIT (wild type and D816V mutant), platelet-derived growth factor (PDGF) receptor α/β, and vascular endothelial growth factor receptor 2, as well as members of the serine/threonine kinase protein kinase C family. Midostaurin has been found to inhibit FLT3 receptor signaling and cell proliferation and induce apoptosis in leukemic cells expressing internal tandem duplication and tyrosine kinase domain–mutant FLT3 receptors or overexpressing wild-type FLT3 and PDGF receptors and to inhibit KIT signaling, cell proliferation, and histamine release and induce apoptosis in mast cells. 

How It Is Used 

THE RECOMMENDED DOSE of midostaurin in AML is 50 mg twice daily with food on days 8 to 21 of each cycle of induction and consolidation chemotherapy followed by 50 mg with food as a single agent for up to 12 months. The recommended dose for the treatment of adults with systemic mastocytosis is 100 mg twice daily with food, with treatment continuing until disease progression or unacceptable toxicity. 

Dosing modification in patients with systemic mastocytosis includes interruption of treatment for neutropenia, thrombocytopenia, and anemia, with dose reduction to 50 mg twice daily upon recovery and a subsequent increase back to 100 mg twice daily if tolerated. Treatment should be discontinued for neutropenia, thrombocytopenia, or anemia persisting for more than 21 days and believed to be due to midostaurin. Patients should be monitored for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter. 

Patients receiving midostaurin should receive prophylactic antiemetics before treatment. Monitoring of QT interval should be considered in patients taking concomitant medications that can prolong the QT interval. 

Coadministration of midostaurin and strong CYP3A4 inducers (eg, carbamazepine, enzalutamide (Xtandi), mitotane, phenytoin, rifampin, St. John’s wort) should be avoided. Alternatives to strong CYP3A4 inhibitors (eg, boceprevir [Victrelis], clarithromycin, cobicistat, conivaptan [Vaprisol], diltiazem, grapefruit juice, idelalisib [Zydelig], itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir [Viracept], and tipranavir) should be considered in patients receiving midostaurin; if a strong CYP3A4 inhibitor cannot be avoided, patients should be monitored for an increased risk of midostaurin-related adverse reactions. 

Safety Profile 

IN THE PHASE III TRIAL in AML, data on only grade 3 or 4 adverse events were collected at North American study sites. Among 455 patients at other study sites, the most common adverse events of any grade were febrile neutropenia (83% vs 81% in placebo group), nausea (83% vs 70%), mucositis (66% vs 62%), and vomiting (61% vs 53%). The most common grade ≥ 3 adverse events were febrile neutropenia (84% vs 83%), device-related infection (16% vs 10%), and mucositis (11% vs 13%). The most common grade 3 or 4 laboratory abnormalities were increased alanine transaminase levels (20% vs 16%) and hypocalcemia (7% vs 8%). The most common serious adverse event was febrile neutropenia (16% vs 16%). 

Adverse events led to treatment discontinuation in 9% vs 6%. Among 205 patients (120 in the midostaurin group, 85 in the placebo group) who remained in remission following completion of consolidation and continued to receive study treatment for a median of 11 months, adverse events of any grade that occurred in ≥ 5% of midostaurin patients included nausea (47% vs 18%), hyperglycemia (20% vs 13%), and vomiting (19% vs 5%). Sepsis caused death in 2% of each group, with none of the deaths considered related to treatment. 

Safety data in systemic mastocytosis came from 142 patients receiving 100 mg twice daily in 2 single-arm studies. The most common adverse events of any grade were nausea (82%), vomiting (68%), diarrhea (54%), edema (40%), musculoskeletal pain (35%), abdominal pain (34%), fatigue (34%), and upper respiratory tract infection (30%). The most common grade ≥ 3 adverse events were fatigue (9%), sepsis (9%), gastrointestinal hemorrhage (9%), pneumonia (8%), diarrhea (8%), and febrile neutropenia (8%). The most common grade ≥ 3 laboratory abnormalities were lymphopenia (42%), anemia (38%), thrombocytopenia (27%), and neutropenia (22%). 

Adverse events led to dose modification in 56% of patients, with the most common causes (> 5%) being gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, increased lipase, and fatigue. The median time to the first dose modification for toxicity was 1.6 months, with 75% of dose modifications occurring within 5 months of starting treatment. Treatment was discontinued due to adverse events in 21%, with the most common causes being infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage. Serious adverse events occurred in 68%, most commonly due to infections and gastrointestinal disorders. Deaths unrelated to underlying malignancy occurred in 16 patients (11%), most commonly due to infection (sepsis or pneumonia), followed by cardiac events. 

Midostaurin carries warnings/precautions for pulmonary toxicity, including fatal cases, and embryofetal toxicity. It is contraindicated in patients with hypersensitivity to midostaurin or any of its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema. ■

REFERENCES 

1. U.S. Food and Drug Administration: Midostaurin (Rydapt). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555756.htm. Accessed August 23, 2017. 

2. Rydapt (midostaurin) capsules prescribing information, Novartis Pharmaceuticals Corp, April 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf. Accessed August 23, 2017.