In QuANTUM-First, a randomised, double-blind, placebo-controlled, phase III study conducted in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed acute myeloid leukaemia (AML), quizartinib plus standard induction and consolidation treatment and up to 3 years of continuation with quizartinib monotherapy resulted in a statistically significant 16.8 month overall survival (OS) extension compared with standard therapy in the placebo group and a significant reduction in the risk of death.
Clinically meaningful improvements in reduced cumulative incidence of relapse, increased duration of complete remission, and reduction in measurable residual disease (MRD) underlie the OS benefit. Safety of quizartinib was generally manageable, with no new safety signals identified. The findings show the potential to provide an effective and well tolerated treatment option for patients aged 18-75 years with FLT3-ITD-positive newly diagnosed AML, according to Prof. Harry P Erba of the Duke Cancer Institute in Durham, NC, US, and colleagues who published the results on 25 April 2023 in The Lancet.
The authors wrote in the background that AML is a genetically heterogeneous disease with poor clinical outcomes. Mutations in FLT3 are among the most frequently reported genetic alterations in AML. Approximately 25% of patients with newly diagnosed AML have FLT3-ITD mutations and approximately 7% have point mutations in the tyrosine kinase domain (TKD). FLT3-ITD is associated with poor prognosis, including increased risk of relapse and shorter OS versus wild-type FLT3 and FLT3-TKD.
Standard treatments for FLT3-ITD-positive AML include chemotherapy and allogeneic haematopoietic cell transplantation (allo-HCT). Several FLT3-targeted agents, including multikinase inhibitors, have been investigated in patients with FLT3-mutated AML. In 2017, the multikinase inhibitor midostaurin, plus standard chemotherapy, gained US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for the treatment of newly diagnosed AML with either ITD or TKD mutations based on data from the RATIFY study.
Quizartinib is an oral, once per day, highly potent, selective, second-generation, type 2 FLT3 inhibitor. In phase I/II studies, quizartinib plus chemotherapy showed activity with an acceptable safety profile and as a single agent after allo-HCT in patients with FLT3-ITD-positive newly diagnosed AML. Quizartinib as monotherapy improved OS versus salvage chemotherapy in the relapsed or refractory setting in the phase III QuANTUM-R study.
QuANTUM-First is the first study to evaluate the efficacy and safety of a selective FLT3 inhibitor, quizartinib, in patients aged 18-75 years with FLT3-ITD-positive newly diagnosed AML alongside standard induction and consolidation chemotherapy, including allo-HCT, then single-agent continuation treatment for up to 3 years. This study aimed to assess the effect of quizartinib versus placebo on OS in patients with FLT3-ITD-positive newly diagnosed AML. The study team hypothesised that quizartinib would extend OS in these patients.
The study was conducted at 193 hospitals and clinics in 26 countries in Europe, North America, Asia, Australia, and South America. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned.
Induction treatment comprised a standard 7 plus 3 induction regimen of cytarabine 100 mg/m2 per day (or 200 mg/m2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allo-HCT, or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years.
The primary outcome was OS, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo.
Between 27 September 2016 and 14 August 2019, 3468 patients with AML were screened and 539 patients with FLT3-ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). A total, 148 of 268 patients (55%) in the quizartinib group and 168 of 271 patients (62%) in the placebo group discontinued the study, primarily because of death or withdrawal of consent. Median age was 56 years (range, 20–75).
At a median follow-up of 39.2 months, median OS was 31.9 months (95% confidence interval [CI] 21.0–not estimable) for quizartinib versus 15.1 months (13.2–26.2) for placebo (hazard ratio [HR] 0.78 (95% CI 0.62–0.98, p = 0.032).
More patients treated with quizartinib (42%) than with placebo (38%) were MRD negative at the time of complete remission or complete remission with incomplete neutrophil or platelet recovery. Patients in both groups who were MRD negative had improved OS (HR 0.57, 95% CI 0.40–0.80) compared with those who remained MRD positive.
Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event, and one grade 3 or higher adverse event. The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group.
The authors commented that the placebo comparator group is one limitation of QuANTUM-First, considering that midostaurin plus chemotherapy has been the standard of care since 2017. However, when QuANTUM-First began in 2016, no FLT3 inhibitor was approved for FLT3-mutated newly diagnosed AML, and there was a lack of randomised data in people aged 60 years or older. Therefore, at that time, chemotherapy plus placebo was chosen as the appropriate comparator. Furthermore, the data monitoring committee reviewed the RATIFY data and recommended continuing the QuANTUM-First study as originally designed, maintaining the placebo group.
Another limitation is the low enrolment in North America, probably because midostaurin received US approval 7 months after the start of QuANTUM-First, whereas it received EMA approval 12 months after the start of QuANTUM-First. Enrolment in the EU was not affected as much as enrolment in the US, probably because in some EU countries, reimbursement for midostaurin was granted by health technology assessment agencies up to 3 years after its approval.
The authors concluded that addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved OS in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the study results, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML.
In an accompanied editorial article, Amanda C Przespolewski and Elizabeth A Griffiths of the Roswell Park Comprehensive Cancer Center in Buffalo, NY, US wrote that quizartinib was not favourable to placebo in terms of event-free survival (EFS), but was favourable to placebo with the original protocol definition of EFS of not having complete remission or composite complete remission by the end of induction up to day 56; therefore, these other secondary outcomes are reported descriptively. Later recovery for patients treated with quizartinib is presumably due to the increased myelosuppression conferred from FLT3 inhibition.
The QuANTUM-First study of the selective ITD-specific FLT3 inhibitor quizartinib in combination with chemotherapy in patients with FLT3-ITD-positive newly diagnosed AML supports the safety and utility of upfront FLT3-ITD-specific inhibition in younger and older patients with AML who are fit for intensive chemotherapy, expanding applicability according to the editorialists. The once-per-day dosing schedule for this agent could be argued to represent an advance beyond the current standard of care.
The data from this study also affirm the value of early MRD testing for patients with AML and suggest a strategy whereby therapy might be modified early to optimise long-term response. Long-term outcomes for patients on maintenance who have had a transplantation, as well as detailed molecular response data, are anticipated and could have real implications for patient management. Questions that remain include which FLT3 inhibitor is best in the upfront chemotherapy setting as results from other phase III studies are awaited, in whom and how post-transplant maintenance therapy can be optimised, and what is the ideal approach for older patients or patients with FLT3-positive newly diagnosed AML who are not eligible for a transplantation.
The study was funded by Daiichi Sankyo.
References
- Erba HP, Montesinos P, Kim H-J, et al. on behalf of the QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, doubleblind, placebo-controlled, phase 3 trial. The Lancet; Published online 25 April 2023. DOI: https://doi.org/10.1016/ S0140-6736(23)00464-6.
- Przespolewski AC, Griffiths EA. FLT3-mutated acute myeloid leukaemia: a new opportunity. The Lancet; Published online 25 April 2023. DOI: https://doi.org/10.1016/S0140-6736(23)00617-7.