Daiichi Sankyo Submits sNDA for Quizartinib in Newly Diagnosed FLT3-ITD+ AML in Japan

Drug maker Daiichi Sankyo has submitted a supplemental new drug application (sNDA) to Japan’s Ministry of Health, Labor, and Welfare (MHLW) for the use of quizartinib in patients with newly diagnosed, FLT3-ITD–positive acute myeloid leukemia (AML).¹

The sNDA is based on results from the phase 3 QuANTUM-First trial (NCT02668653), where findings showed that the combination of quizartinib plus standard induction and consolidation chemotherapy followed by quizartinib alone induced a 22.4% reduction in the risk of death compared with standard chemotherapy alone (HR, 0.776; 95% CI, 0.615-0.979; 2-sided P = .0324).² At a median follow-up of 39.2 months, patients in the quizartinib arm achieved a median overall survival (OS) of 31.9 months (95% CI, 21.0–not estimable [NE]), compared with 15.1 months (95% CI, 13.2-26.2) for patients given chemotherapy alone.

“There is continued need in Japan for new therapeutic options to improve survival for patients with FLT3-ITD–positive AML, which is an aggressive and difficult-to-treat subtype,” Wataru Takasaki, PhD, executive officer and head of R&D Division of Daiichi Sankyo in Japan, stated in a press release. “Quizartinib has potential to change the current standard of care as the first FLT3 inhibitor approved in Japan for patients with newly diagnosed FLT3-ITD–positive AML. We look forward to working with the Japan MHLW with the aim to bring quizartinib to physicians and patients in this new indication as soon as possible.”

The international, randomized, double-blind, placebo-controlled QuANTUM-First trial enrolled patients aged 18 to 75 years old with newly diagnosed, FLT3-ITD–positive AML. FLT3-ITD positivity was defined as at least a 3% allelic frequency of FLT3-ITD.³

All patients received 7+3 chemotherapy during screening before being randomly assigned 1:1 to 40 mg of quizartinib on days 8 to 21 or placebo plus standard chemotherapy featuring cytarabine on days 1 to 7 and daunorubicin or idarubicin on days 1 to 3 as induction treatment for up to 2 cycles. Consolidation treatment included high-dose cytarabine plus quizartinib or placebo and/or transplant. Quizartinib or placebo monotherapy was then given once daily for up to 36 cycles.

The primary end point of the trial was OS. Secondary end points included event-free survival (EFS), complete remission (CR), composite CR, and safety. Exploratory end points comprised relapse-free survival and duration of CR.

Additional data from QuANTUM-First showed that the primary EFS analysis, with induction treatment failure (ITF) defined as not achieving a CR by day 42, did not produce a statistically significant difference between the 2 treatment arms. Quizartinib did elicit a benefit when analyzing EFS by defining ITF as not achieving a CR by the end of induction (HR, 0.818; 95% CI, 0.669-0.999) or ITF as not achieving a composite CR by the end of induction (HR, 0.729; 95% CI, 0.592-0.897).²

Patients in the quizartinib arm experienced higher rates of composite CR (71.6% vs 64.9%) compared with the placebo arm, and the rates of CR were similar between the 2 arms (54.9% and 55.4%). The median duration of CR for quizartinib was 38.6 months (95% CI, 21.9-NE), compared with 12.4 months (95% CI, 8.8-22.7) for the placebo arm.

The median RFS for patients who achieved a CR was 39.3 months in the quizartinib arm vs 13.6 months for the placebo arm (HR, 0.613; 95% CI, 0.444-0.845).

Regarding safety, the addition of quizartinib to intensive chemotherapy and as continuation as a single agent was manageable, and no new safety signals were observed. The incidence of grade 3 or higher QT prolongation was low, and ventricular arrythmia events were uncommon. The risk of QT prolongation was manageable with ECG monitoring, quizartinib dose modification, and correction/elimination of additional risk factors.

In June 2019, Japan approved quizartinib for the treatment of adult patients with relapsed/refractory FTL3-ITD—positive AML as detected by an MHLW-approved assay, based on findings from the phase 3 QuANTUM-R trial (NCT02039726), which evaluated single-agent quizartinib vs salvage chemotherapy.⁴

References

1. Quizartinib supplemental new drug application submitted in Japan for patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia. News release. Daiichi Sankyo. August 30, 2022. Accessed August 30, 2022. https://bit.ly/3AWQciR
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 30, 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 30, 2022. https://clinicaltrials.gov/ct2/show/NCT02668653
4. Daiichi Sankyo’s VANFLYTA® Receives Approval in Japan for the Treatment of Relapsed/Refractory FLT3-ITD AML. Daiichi Sankyo. June 18, 2019. Accessed August 30, 2022. https://bit.ly/3q0EaPa