Quizartinib Garners Approval in Japan for Newly Diagnosed FLT3-ITD+ AML

Japan’s Ministry of Health, Labour, and Welfare has approved quizartinib (Vanflyta) in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation and as maintenance monotherapy in patients with newly diagnosed acute myeloid leukemia (AML) whose tumors harbor FLT3-ITD mutations.¹

The regulatory decision is supported by data from the phase 3 QuANTUM-First trial (NCT02668653) in which the addition of the agent to standard chemotherapy with or without allogeneic hematopoietic cell transplantation, followed by continued monotherapy for up to 3 years, led to a significant improvement in overall survival (OS) over placebo in this patient population.²

At a median follow-up of 39.2 months (interquartile range, 31.9-45.8), the median OS in the investigative arm (n = 268) was 31.9 months (95% CI, 21.0-not estimable) vs 15.1 months (95% CI, 13.2-26.2) in the control arm (n = 271; HR, 0.78; 95% CI, 0.62-0.98; P = .032).

“Patients with newly diagnosed FLT3-ITD positive AML now will have the opportunity to receive targeted therapy with [quizartinib],” Wataru Takasaki, PhD, executive officer and head of the R&D Division at Daiichi Sankyo in Japan, stated in a press release.¹ “[Quizartinib] is the only medicine developed and approved specifically for treatment of newly diagnosed FLT3-ITD–positive AML in Japan and has demonstrated improved OS for this patient population.”

The randomized, double-blind, placebo-controlled phase 3 trial enrolled patients with primary newly diagnosed AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm harboring a FLT3-ITD mutation who were between the ages of 18 years and 75 years.² Patients needed to have an ECOG performance status of 0 to 2, a variant allelic frequency of 3% or higher, and acceptable renal, cardiac, and hepatic function.

Study participants received standard 7+3 induction with cytarabine at 100 mg/m² daily continuously via infusion from days 1 to 7 and an anthracycline via infusion on days 1 to 3. On day 7, they were randomly assigned to quizartinib or placebo. On day 8, patients received oral quizartinib at a daily dose of 40 mg or placebo for the duration of 14 days.

Stratification factors included region (Europe vs North America vs Asia, Australia, and South America), age (under 60 years vs 60 years and older), and white blood cell count at diagnosis (<40 x 10⁹/L vs ≥40 x 10⁹/L).

OS served as the primary end point, and secondary end points comprised event-free survival (EFS), post-induction rates of complete remission (CR) and composite CR (CRc), and the percentage of patients who achieved CR or CRc with FLT3-ITD measurable residual disease negativity. Investigators also evaluated safety, pharmacokinetics, and other exploratory end points.

Demographics and disease characteristics of the participants were well balanced between the arms and were noted to be reflective of the FLT3-ITD–positive AML population.

The median age was 56 years (range, 20-75). In the investigative and control arms, 54% and 55% of patients, respectively, were female; 59% and 60% were White; 61% and 60% were from Europe; 50% and 50% had an ECOG performance status of 1; 91% and 94% had de novo disease; and 74% and 71% had intermediate cytogenetic risk.

The hazard ratio for EFS was 0.92 (95% CI, 0.75-1.11; P = .24).

The median duration of CR was extended with quizartinib vs placebo, at 38.6 months (95% CI, 21.-9-not evaluable [NE]) and 12.4 months (95% CI, 8.8-22.7), respectively (HR, 0.62; 95% CI, 0.45-0.86). In those who experienced a CR during induction treatment, relapse-free survival was also prolonged with quizartinib over placebo, at a median of 39.3 months (95% CI, 22.6-NE) and 13.6 months (95% CI, 9.7-23.7; HR, 0.61; 95% CI, 0.44-0.85).

Moreover, reduced cumulative incidences of relapse were reported in those with CR who received quizartinib vs those who received placebo at 12 months, at 18.7% (95% CI, 12.7%-25.6%) and 34.9% (95% CI, 27.1%-42.7%), respectively; at 24 months, these rates were 31.2% (95% CI, 23.5%-39.2%) and 43.3% (95% CI, 34.9%-51.3%), respectively.

The toxicity profile of quizartinib proved to be consistent with what has previously been reported, with no new signals observed. The most common toxicities reported in 265 patients who received the agent on the trial included neutropenia (25%), thrombocytopenia (22.7%), nausea (20.6%), and electrocardiogram QT prolonged (19.3%).¹

In October 2022, the FDA granted a priority review to a new drug application seeking the approval of quizartinib in the same patient population.³ The original Prescription Drug User Fee Act was April 24, 2023, but the target action date has been extended by 3 months to allow for additional time to review requested updates to the proposed risk evaluation and mitigation strategies included in the application.⁴ The new decision date is July 24, 2023.

References

1. Vanflyta first FLT3 inhibitor approved in Japan for patients with newly diagnosed FLT3-ITD positive AML. News release. Daiichi Sankyo. May 25, 2023. Accessed May 25, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202305/20230525_E.pdf
2. Erba HP, Montesinos P, Kim H-J, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10388):1571-1583. doi:10.1016/S0140-6736(23)00464-6
3. Quizartinib granted priority review in the US for patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia. News release. Daiichi Sankyo. October 24, 2022. Accessed May 25, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202210/20221024_E2.pdf
4. Quizartinib NDA review for patients with newly diagnosed FLT3- ITD positive AML extended by FDA. News release. Daiichi Sankyo. April 20, 2023. Accessed May 25, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202304/