CHMP Releases Positive Opinion for Quizartinib in Newly Diagnosed FLT3-ITD+ AML

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of quizartinib (Vanflyta) in the European Union (EU) for use in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by quizartinib monotherapy as maintenance, for adult patients with newly diagnosed, FLT3-ITD–positive acute myeloid leukemia (AML).¹

The recommendation for approval was based on findings from the phase 3 QuANTUM-First trial (NCT02668653),² in which the addition of quizartinib to standard cytarabine and anthracycline induction and standard cytarabine consolidation, and continued as maintenance monotherapy, improved overall survival (OS) vs standard chemotherapy alone (HR, 0.78; 95% CI, 0.62-0.98; P =.032) in patients with newly diagnosed FLT3-ITD positive AML. At a median follow-up of 39.2 months (interquartile range [IQR], 31.9-45.8), median OS was 31.9 months (95% CI, 1.0-not evaluable) with quizartinib (n = 268) vs 15.1 months (95% CI: 13.2-26.2) with chemotherapy alone (n = 271).

“Today’s positive CHMP opinion for quizartinib is an important step towards translating the clinical benefit observed in QuANTUM-First into an approved treatment option for patients in the EU with the difficult-to-treat FLT3-ITD subtype of acute myeloid leukemia,” Mark Rutstein, MD, global head, Oncology Clinical Development, Daiichi Sankyo, stated in a news release. “If approved, quizartinib would be the first FLT3 inhibitor approved specifically for patients with newly diagnosed FLT3-ITD positive AML.”¹

Data from QuANTUM-First served as the basis for the July 20, 2023, FDA approval of quizartinib plus standard induction and consolidation, and as maintenance monotherapy following consolidation chemotherapy, in patients with newly diagnosed AML that is FLT3-ITD positive, as detected by an FDA-approved test.³

QuANTUM-First is a randomized, double-blind, placebo-controlled, global phase 3 study evaluating quizartinib plus standard induction and consolidation therapy, including hematopoietic stem cell transplant (HSCT), and as maintenance monotherapy, in 539 adult patients aged 18 to 75 with newly diagnosed FLT3-ITD positive AML.

Patients were randomly assigned 1:1 to receive quizartinib or placebo plus cytarabine and anthracycline induction and cytarabine consolidation chemotherapy followed by up to 3 years of treatment with quizartinib or placebo, respectively.

In addition to the primary end point of OS, secondary end points include event-free survival, postinduction rates of complete remission (CR) and composite complete remission (CRc), and the percentage of patients who achieve CR or CRc with FLT3-ITD measurable residual disease negativity. Safety, pharmacokinetics, and other efficacy and biomarker end points including duration of CR were also evaluated.

Median patient age was 56 years (range, 20-75; IQR, 46.0-65.0). Most patients in both arms were under the age of 60, female, and White. Half of patients had an ECOG performance status of 1, and the majority had de novo AML and intermediate risk. The predominant region of enrollment was Europe.²

Additional results from the prespecified OS sensitivity analysis, which censored patients who received allogeneic transplant at any time, demonstrated similar benefit with quizartinib (HR, 0.75; 95% CI, 0.56-1.01). Notably, greater benefit was seen in patients younger than 60 years (HR, 0.68; 95% CI, 0.49-0.95) vs patients aged 60 years or older (HR, 0.91; 0.66-1.26) in a post-hoc subgroup analysis.

EFS was not statistically significant (HR, 0.92; 95% CI, 0.75-1.11; P =.24). Therefore, all subsequent analyses on other secondary end points did not undergo formal hierarchical testing.

Descriptive analysis indicated that the CR rate with quizartinib (95% CI, 48.7%-60.9%) and chemotherapy alone (95% CI, 49.2%-61.4%) was 55%. The median duration of CR with quizartinib was 38.6 months (95% CI, 21.9-NE) vs 12.4 months (95% CI, 8.8-22.7) with chemotherapy alone.²

Regarding safety, no new signals were reported with the investigational regimen. The median treatment duration was 10.71 weeks (IQR, 2.29-70.86) with quizartinib and 9.50 weeks (IQR, 2.14-42.14) with placebo.

The most frequent grade 3 or 4 treatment-emergent adverse effects that occurred in at least 10% of patients on quizartinib were febrile neutropenia (43%), hypokalemia (19%), neutropenia (18%), and pneumonia (11%).¹

A total of 2.3% of patients who received quizartinib had QTcF above 500 ms, 0.8% of whom discontinued treatment because of prolonged QT interval. Ventricular arrhythmia events with quizartinib were rare. However, both (0.8%) cases of cardiac arrest with recorded ventricular fibrillation on ECG occurred in the setting of severe hypokalemia, one of which proved fatal.

References

1. Quizartinib recommended for approval in EU by CHMP for patients with newly diagnosed FLT3-ITD positive AML. News release. Daiichi Sankyo. September 15, 2023. Accessed September 15, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202309/20230915_E2.pdf
2. Erba HP, Montesinos P, Kim HJ, 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. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. News release. FDA. July 20, 2023. Accessed September 15, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia