EMA Validates Marketing Authorization Application for Quizartinib in Newly Diagnosed FLT3-ITD+ AML

Ken Takeshita, MD

The European Medicines Agency (EMA) has validated the marketing authorization application (MAA) for quizartinib in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, for the treatment of adult patients with newly diagnosed FLT3-ITD–mutated acute myeloid leukemia (AML).¹

The MAA was based on data from the phase 3 QuANTUM-First trial (NCT02668653), which showed that the addition of quizartinib to standard induction and consolidation chemotherapy and then continued as a single agent doubled median overall survival (OS) vs standard chemotherapy alone in patients with newly diagnosed FLT3-ITD–positive AML.²

At a median follow-up of 39.2 months, patients in the quizartinib arm achieved a median OS of 31.9 months (95% CI, 21.0–not estimable) compared with 15.1 months (95% CI, 13.2-26.2) in the placebo arm, leading to a 22.4% reduction in the risk of death (HR, 0.776; 95% CI, 0.615-0.979; 2-sided P = .0324).

“There is a need to improve survival for the majority of patients with AML, particularly those with the FLT3-ITD subtype, which is aggressive and difficult to treat,” Ken Takeshita, MD, the global head of R&D at Daiichi Sankyo, stated in a press release. “We look forward to working with the EMA to support their review of quizartinib as a potential option for patients with newly diagnosed FLT3-ITD–positive AML.”

The international, double-blind, placebo-controlled QuANTUM-First trial enrolled patients between the ages of 18 years and 75 years who had newly diagnosed FLT3-ITD–positive AML.³ Patients were required to have at least a 3% FLT3-ITD allelic frequency. Additional inclusion criteria included an ECOG performance status of 2 or less, the administration of 7+3 induction chemotherapy during screening, and adequate renal and hepatic function.

Patients were excluded from the trial if they received prior treatment for AML, except for leukapheresis, treatment for hyperleukocytosis with hydroxyurea, cranial radiotherapy for central nervous system leukostasis, prophylactic intrathecal chemotherapy, or growth factor/cytokine support. Patients were also not allowed to have prior exposure to quizartinib or other FLT3-ITD inhibitors.

Enrolled patients were randomized 1:1 to received 40 mg of quizartinib on days 8 through 21 or placebo added to standard chemotherapy, which included cytarabine on days 1 to 7 and daunorubicin or idarubicin on days 1 to 3 as induction treatment for up to 2 cycles. Patients then received consolidation treatment with high-dose cytarabine plus quizartinib or placebo and/or transplant. Single-agent quizartinib or placebo was then given once daily for up to 36 cycles.

OS served as the primary end point of the trial, and secondary end points included event-free survival, complete remission (CR), composite CR, and safety. Relapse-free survival and duration of CR served as exploratory end points.

Regarding safety, the addition of quizartinib to intensive chemotherapy and as continuation monotherapy in QuANTUM-First was generally manageable and consistent with previous clinical trials. Rates of grade 3 or higher QT prolongation was low, and the risk of QT prolongation was manageable with ECG monitoring, quizartinib dose modification and correction/elimination of additional risk factors.

References

1. Quizartinib marketing authorization application validated by EMA for treatment of adult patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia. News release. Daiichi Sankyo. August 23, 2022. Accessed August 23, 2022. https://bit.ly/3c9KqkI
2. Quizartinib plus chemotherapy significantly improved overall survival compared to chemotherapy in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia. News release. Daiichi Sankyo. June 11, 2022. Accessed August 23, 2022. https://bit.ly/3O3kzbc
3. Quizartinib with standard of care chemotherapy and as continuation therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First). ClinicalTrials.gov. Updated April 15, 2022. Accessed August 23, 2022. https://clinicaltrials.gov/ct2/show/NCT02668653