FDA Extends Decision Date on Quizartinib for FLT3-ITD-Positive AML


The new Prescription Drug User Fee Act action date for quizartinib for use in patients with newly diagnosed FLT3-ITD-positive acute myeloid leukemia has been set to July 24, 2023.

The FDA has extended the review period for the new drug application (NDA) of 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) by 3 months, according to Daiichi Sankyo.1

The extension has now set the Prescription Drug User Fee Act (PDUFA) action date to July 24, 2023. This will allow additional time for the company and FDA to review requested updates to the proposed Risk Evaluation and Mitigation Strategies (REMS) included in this application. No additional efficacy or safety data have been requested.

The QuANTUM-First trial (NCT02668653) is the basis of this NDA as findings revealed that this combination of quizartinib combined and continuation as monotherapy following consolidation led to a statistically significant and clinically meaningful improvement in overall survival in adult patients with newly diagnosed FLT3-ITD positive AML compared with chemotherapy alone. Results of the QuANTUM-First study were presented at the 2022 European Hematology Association (EHA) Congress.

"We are continuing to work with the FDA to facilitate completion of their review of the quizartinib new drug application in order to bring this important medicine to patients as soon as possible," said Mark Rutstein, MD, global head, oncology clinical development, Daiichi Sankyo, in the press release. "Quizartinib was shown to improve overall survival when added to standard chemotherapy and continued as monotherapy and has potential to change the standard of care for patients with newly diagnosed FLT3-ITD positive AML."

Quizartinib is an oral, highly potent type II FLT3 inhibitor that works by selectively targeting FLT3-ITD mutations. The agent has been specifically developed for patients with FLT3-ITD positive AML.

In the randomized, double-blind, placebo-controlled, global, phase 3 QuANTUM-First study, quizartinib in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, is being assessed for the treatment of adult patients aged 18-75 with newly diagnosed FLT3-ITD-positive AML.2

The trial randomized patients 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. Patients were then given consolidation treatment with high-dose cytarabine combined with quizartinib or placebo and/or transplant per institutional policies, followed by quizartinib or placebo monotherapy given once a day for up to 36 cycles.

Patients were eligible for enrollment in the study if they underwent hematopoietic stem cell transplant (HSCT), continued with quizartinib or placebo for up to 36 cycles. At baseline, patients were balanced between the arms with the median age of patients at 56 years (range, 20-65) between arms. Approximately 54% of patients were male, most patients were White, and most were from Europe.

The primary end point of the study was overall survival with secondary end points of event-free survival, post-induction rates of complete remission (CR) and composite complete remission (CRc), and the percentage of patients who achieve CR or CRc with FLT3-ITD minimal residual disease negativity. Other exploratory end points were safety, pharmacokinetics, and efficacy and biomarker end points.

In the primary analysis of EFS, the HR was 0.916 (95% CI, 0.754-1.114; P = .2371).3 The sensitivity analysis of EFS showed an HR of 0.818 (95% CI, 0.669-0.999; P = .0323), and the hierarchical testing procedure was stopped after EFS as the primary EFS result was not statistically significant. 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).

Quizartinib led to a CRc of 71.6% (95% CI, 65.8%-77.0%) vs 64.9% (95% CI, 58.9%-70.6%) with placebo, and 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. 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.

Grade 3 or higher treatment-emergent adverse events (TEAEs) were similar between both study arms. The most common grade 3 or higher TEAEs which occurred in at least 10% of patients were 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%). Additionally, 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, with no new safety signals reported.

1. Quizartinib NDA review for patients with newly diagnosed FLT3-ITD positive AML extended by FDA. News release. Daiichi Sankyo. April 20, 2023. Accessed April 21, 2023. https://yhoo.it/41K72w6
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 December 29, 2022. Accessed April 21, 2023. https://clinicaltrials.gov/ct2/show/NCT02668653
3. Erba H, Montesinos P, Vrhovac R, et al. Quizartinib prolongs survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria
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