Quizartinib with standard induction and consolidation chemotherapy followed by continued quizartinib monotherapy treatment led to significant improvement in overall survival in patients with newly diagnosed FLT3-ITD–positive acute myeloid leukemia.
Treatment of quizartinib (AC220) with standard induction and consolidation chemotherapy and then continued quizartinib monotherapy treatment led to significant improvement in overall survival (OS) in adult patients with newly diagnosed FLT3-ITD–positive acute myeloid leukemia (AML) compared to patients who received chemotherapy alone.1
Investigators examined a 22.4% reduction in the risk of death with this quizartinib regimen compared with standard chemotherapy treatment (HR, 0.776; 95% CI, 0.615-0.979; 2-sided P = 0.324). The median OS was 31.9 months (95% CI, 21.-not estimable [NE]) for the experimental group and was 15.2 months (95% CI, 13.2-26.2) for the control group at a median follow-up of 39.2 months.
QuANTUM-First (NCT02668653) is a phase 3 randomized, double-blind, placebo-control global study. This trial enrolled and randomized 539 patients to receive a quizartinib plus chemotherapy regimen or chemotherapy alone. The study regimen consisted of up to 2 cycles of cytarabine and daunorubicin/idarubicin followed by quizartinib, then up to 4 cycles of cytabine followed by quizartinib and/or hematopoeitic stem cell transplant (HSTC), and finished with up to 36 cycles of quizartinib. The primary end point of the study is OS, and the secondary end points include event-free survival (EFS), complete remission (CR) rate, and composite CR (CRc).2
A sensitivity analysis which censored the effect of the allogenic HSCT supported the observed OS improvement (HR, 0.752; 95% CI, 0.562-1.008).
EFS analysis showed no statistically significant difference between patients in the quizartinib arm and the control arm, however, in an EFS analysis with induction treatment failure (ITC) defined as not achieving CR by the end of induction (HR, 0.818; 95% CI: 0.669-0.999) or in an EFS analysis where ITF was defined as not achieving CRc by the end of induction (HR, 0.729; (95% CI, 0.592-0.897).
Patients in the quizartinib group had a CRc rate of 71.6% vs 64.9% in patients in the chemotherapy alone group. CR rates were similar with 54.9% in the quizartinib arm compared with 55.4% in the chemotherapy arm. The median duration of CR was 38.6 months (95% CI, 21.9-NE) for the quizartinib arm and 12.4 months (95% CI, 8.8-22.7) for the chemotherapy arm.
The median relapse-free survival (RFS) for patients who achieved CR was 39.3 months for quizartinib and 13.6 months for the control arm. This finding signified a 38.7% relative risk reduction of relapse or death (HR, 0.613; 95% CI, 0.444-0.845).
"The QuANTUM-First results show that adding quizartinib to standard chemotherapy significantly improved overall survival in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia," Harry P. Erba, MD, PhD, Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute said. "There is great interest in the increased use of targeted therapies to improve outcomes for patients with AML, particularly those with the FLT3-ITD subtype, which is one of the most common, aggressive and difficult-to-treat."
Safety in the experimental arm was manageable, displaying no new safety signals. Grade 3 treatment-emergent adverse events (TEAEs) were similar in both treatment arms. Grade 3 febrile neutropenia occurred in 43.4% of patients with quizartinib vs 41.0% of patients with chemotherapy alone, neutropenia in 18% and 8.6%, respectively, hypokalemia in 18.9% and 16.4%, respectively, and pneumonia in 11.7% and 12.7%, respectively.TEAEs associated with fatal outcomes were observed in 11.3% patients receiving quizartinib and in 9.7% of patients receiving chemotherapy alone. These fatal events were mainly a result of infections.
Investigators recorded cardiac arrest in 2 patients (0.8%) with ventricular fibrillation on electrocardiogram who received quizartinib. One of the cardiac arrest events resulted in death, and both events were in the setting of severe hypokalemia.
"We are proud that another one of our medicines has demonstrated a significant survival advantage, as our goal is to leverage innovative science to change the way cancer is treated," Ken Takeshita, MD, global head, Research and Development at Daiichi Sankyo said. "Adding targeted treatment with quizartinib, a potent and selective FLT3 inhibitor, to standard chemotherapy resulted in a doubling of median overall survival in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia compared to standard chemotherapy alone. Based on these positive QuANTUM-First results, we have initiated global regulatory filings in order to bring quizartinib to patients as quickly as possible."