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

The FDA has accepted and 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 the treatment of newly diagnosed adult patients with FLT3-ITD–positive acute myeloid leukemia (AML).¹

The NDA was based on findings from the phase 3 QuANTUM-First trial (NCT02668653), where data showed that quizartinib plus standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and continued as monotherapy following consolidation, demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in adult patients with newly diagnosed FLT3-ITD–positive AML compared with chemotherapy alone.

Data presented at the 2022 EHA Congress showed that at a median follow-up of 39.2 months, patients treated 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) for those in the placebo arm, translating to a 22.4% reduction in the risk of death (HR, 0.776; 95% CI, 0.615-0.979; 2-sided P = .0324).²

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

“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,” 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”

The randomized, double-blind, placebo-controlled, global QuANTUM-First trial enrolled patients aged 18 to 75 years with newly diagnosed FLT3-ITD–positive AML who had a FLT3-ITD allelic frequency of at least 3%.³

Patients began 7+3 chemotherapy during screening before being randomly assigned to receive induction therapy with 40 mg of quizartinib or placebo on days 8 through 21 plus cytarabine on days 1 to 7 and daunorubicin or idarubicin on days 1 to 3 for up to 2 cycles. Consolidation treatment included high-dose cytarabine plus quizartinib or placebo and/or transplant, per institutional policies. Quizartinib or placebo monotherapy was then given once daily for up to 36 cycles.

OS served as the trial’s primary end point. Secondary end points included event-free survival (EFS), complete remission (CR), composite CR (CRc), and safety. Relapse-free survival (RFS) and duration of CR comprised exploratory end points.

Additional data from the primary EFS analysis did not show a statistically significant difference between the two study arms for the 2 prespecified sensitivity analyses on EFS, which defined induction treatment failure (ITF) as not achieving CR by the end of induction (HR, 0.818; 95% CI, 0.669-0.999) and ITF as having not achieving CRc by the end of induction (HR, 0.729; 95% CI, 0.592-0.897).

Patients receiving quizartinib experienced a CRc rate of 71.6% compared with 64.9% for chemotherapy alone. The rates of CR were 54.9% and 55.4% for the quizartinib and placebo arms, respectively. The median duration of CR in the quizartinib arm was 38.6 months (95% CI, 21.9-NE) vs 12.4 months (95% CI, 8.8-22.7) for chemotherapy.

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

Regarding safety, the quizartinib plus intensive chemotherapy regimen was generally manageable, with no new safety signals observed. 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 occurring in at least 10% of patients were febrile neutropenia (43.4% and 41.0% in the quizartinib and placebo arms, respectively), 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.

References

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://bit.ly/3VUJUcb
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 October 24, 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 October 5, 2022. Accessed October 24, 2022. https://clinicaltrials.gov/ct2/show/NCT02668653