FDA Grants Priority Review to Quizartinib NDA for FLT3-ITD–Positive AML

Based on data from the phase 3 QuANTUM-First trial, the FDA has accepted and granted priority review to the new drug application for quizartinib for patients with FLT3-ITD-positive acute myeloid leukemia.

The FDA has granted priority review to the new drug application (NDA) for quizartinib in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, for adult patients with newly-diagnosed, FLT3-ITD-positive acute myeloid leukemia (AML), according to Daiichi Sankyo.1

The basis of the NDA comes from findings of the phase 3 QuANTUM-First trial (NCT02668653) which showed that quizartinib combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and continued as monotherapy following consolidation, elicited a statistically significant and clinically meaningful improvement in overall survival (OS) compared with chemotherapy alone when used in this patient population.

In QuANTUM-First, quizartinib combined with intensive chemotherapy and as continuation monotherapy was also generally manageable and no new safety signals observed. Further data presented at the European Hematology Association 2022 Congress showed that at a median follow-up of 39.2 months, patients treated with quizartinib achieved a median OS of 31.9 months (95% CI, 21.0–not estimable) vs 15.1 months (95% CI, 13.2-26.2) for those in the placebo arm, resulting in 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 for new targeted therapy options for patients with AML and the results of the QuANTUM-First trial showed that quizartinib in combination with standard chemotherapy has potential to change the current standard of care for newly diagnosed patients with the historically difficult-to-treat FLT3-ITD subtype,” said Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, stated in a press release. “The FDA’s prioritization of this application reflects the importance of the data, and we will continue to work with the FDA and other global regulatory authorities to support the review of quizartinib for the treatment of patients with newly diagnosed FLT3-ITD positive AML”

QuANTUM-First is a randomized, double-blind, placebo-controlled, global trial which enrolled patients aged 18 to 75 years with newly diagnosed FLT3-ITD–positive AML with at least a 3% FLT3 ITD allelic frequency.2 During screening, patients began 7+3 chemotherapy.

Those enrolled were randomly assigned 1:1 to receive either quizartinib at 40 mg on days 8 through 21 or placebo added to standard chemotherapy in the form of cytarabine on days 1 to 7 and daunorubicin or idarubicin on days 1 to 3 as induction treatment for up to 2 cycles. Then, patients were given consolidation treatment with high-dose cytarabine combined with quizartinib or placebo and/or transplant per institutional policies. Quizartinib or placebo monotherapy was then given once a day for up to 36 cycles.

Stratification factors included region (North America vs European Union vs Asia/other regions), patient age (< 60 years vs ≥ 60 years), and white blood cell count (< 40 x 109/L vs ≥ 40 x 109/L).

The primary end point of the trial was OS and the secondary end points included event-free survival (EFS), complete remission (CR), composite CR (CRc), and safety. Relapse-free survival (RFS) and duration of CR were the exploratory end points of the study.

At the time of the data cutoff of August 13, 2021, a total of 3468 patients were screened and 539 of those patients underwent randomization. A total of 268 patients made up those enrolled to the quizartinib arm while 271 were enrolled to the placebo arm and 265 and 268 patients received treatment, respectively.

In the quizartinib arm, 32 patients were still receiving treatment, 88 were alive and continuing follow-up, and 148 had discontinued treatment. Common reasons for treatment discontinuation included death (n = 133), withdrawn consent (n = 13), and loss to follow-up (n = 2). In the control arm, 26 patients were still receiving treatment, 77 were alive and continuing follow-up, and 168 discontinued. A total of 158 who discontinued treatment died, 9 withdrew consent, and 1 was lost to follow-up.

Baseline patient characteristics were balanced between the arms. The median age was 56 years (range, 20-65) in both arms, and approximately 54% were male. Most patients were White and from Europe.

Data revealed that in the primary analysis of EFS, the HR was 0.916 (95% CI, 0.754-1.114; P = .2371), and in the sensitivity analysis of EFS, the HR was 0.818 (95% CI, 0.669-0.999; P = .0323). The hierarchical testing procedure was stopped after EFS as the primary EFS result was not statistically significant.

Those treated with quizartinib had a CRc of 71.6% (95% CI, 65.8%-77.0%) vs 64.9% (95% CI, 58.9%-70.6%) with placebo. The CR rate for quizartinib was 54.9% (95% CI, 48.7%-60.9%) vs 55.4% (95% CI, 49.2%-61.4%) for placebo, and the CR with incomplete hematologic recovery rates were 16.8% (95% CI, 12.5%-21.8%) and 9.6% (95% CI, 6.4%- 13.7%), respectively. In the investigative arm, the duration of CR was 38.6 months (95% CI, 21.9-not evaluable) vs 12.4 months (95% CI, 8.8-22.7) in the control arm.

The median RFS for patients who achieved CR was 39.3 months for quizartinib and 13.6 months for placebo. This represented a 38.7% relative risk reduction of relapse or death (HR, 0.613; 95% CI, 0.444-0.845).

Regarding safety, rates of grade 3 or higher treatment-emergent adverse effects (TEAEs) were similar for both study groups. The most common grade 3 or higher TEAEs which occurred in at least 10% of patients included febrile neutropenia (43.4% and 41.0% in the quizartinib and placebo arms), neutropenia (18% and 8.6%), hypokalemia (18.9% and 16.4%), and pneumonia (11.7% and 12.7%).

Rates of TEAEs associated with fatal outcomes were 11.3% for quizartinib vs 9.7% for chemotherapy alone, and these deaths were mainly due to infections. The safety of quizartinib in combination with intensive chemotherapy and as continuation monotherapy was found to be manageable and notable, no new safety signals were reported.

The action date for the FDA’s regulatory decision is April 24, 2023, under the Prescription Drug User Fee Act.

  1. Quizartinib granted priority review in the U.S. for patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia. News release. Daiichi Sankyo. October 24, 2022. Accessed October 24, 2022. https://bwnews.pr/3TSQi1Y
  2. 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 October 5, 2022. Accessed October 24, 2022. https://clinicaltrials.gov/ct2/show/NCT02668653
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