AML cells
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to quizartinib, an investigational FLT3 inhibitor, for the treatment of adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).
The FDA granted quizartinib breakthrough designation based on results from the phase 3 QuANTUM-R study, which were presented at the 23rd Congress of the European Hematology Association in June.
QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission.
Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).
Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT. Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.
The median follow-up was 23.5 months. The efficacy results include all randomized patients.
The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The complete response (CR) rate was 4% and 1%, respectively; the rate of CR with incomplete platelet recovery was 4% and 0%, respectively; and the rate of CR with incomplete hematologic recovery was 40% and 26%, respectively.
The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.
The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).
The safety results include only patients who received their assigned treatment—241 patients who received quizartinib and 94 who received salvage chemotherapy (22 on LoDAC, 25 on MEC, and 47 on FLAG-IDA).
Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).
Grade 3 or higher nonhematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).
Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, and 2 patients discontinued quizartinib due to QTcF prolongation.
About breakthrough designation
Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Other designations for quizartinib
In addition to breakthrough therapy designation, quizartinib has fast track and orphan drug designations from the FDA.
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.