The addition of quizartinib to standard induction and consolidation chemotherapy with idarubicin plus cytarabine followed by maintenance therapy led to an improvement in event-free survival compared with placebo plus chemotherapy in patients with FLT3-ITD wild-type acute myeloid leukemia.
The addition of quizartinib (Vanflyta) to standard induction and consolidation chemotherapy with idarubicin plus cytarabine (7+3) followed by maintenance therapy led to an improvement in event-free survival (EFS) and showed an early trend toward improved overall survival (OS) compared with placebo plus chemotherapy in patients with FLT3-ITD wild-type acute myeloid leukemia (AML), according to interim data from the phase 2 QUIWI trial (NCT04107727).
In results that were presented at the 2023 EHA Congress, the median EFS was 16.5 months with quizartinib vs 10.6 months with placebo (HR, 0.741; 95% CI, 0.535-1.026; P =.059). Median OS was not reached (NR) with quizartinib vs 20.2 months with placebo (HR, 0.569; 95% CI, 0.385-0.841; P =.004).
“Preliminary results from the QUIWI trial suggest that quizartinib combined with standard induction and consolidation therapy and continued for up to 12 cycles, may prolong OS in newly diagnosed FLT3-ITD–negative AML,” lead study author Pau Montesinos, MD, PhD, an attending physician and hematologist at the University Hospital La Fe in Valencia, Spain, said in a presentation of the data. “If confirmed, the QUIWI trial results may lead to novel curative approaches for adult patients with newly diagnosed FLT3-ITD–negative AML.”
The FLT3 ligand activates the FLT3 receptor, which is involved in normal hematopoiesis, resulting in stem cell survival and growth. However, the survival and proliferation of AML cells simultaneously depend on FLT3 activation. As such, FLT3 inhibition with oral targeted agents may prove useful for patients with wild-type FLT3.
Previously reported findings from the phase 2 SORAML trial (NCT00893373) demonstrated that the addition of sorafenib (Nexavar) to 7+3 chemotherapy improved leukemia-free survival but not OS in newly diagnosed patients with FLT3-ITD–mutated and wild-type AML who were under the age of 60 years.
Quizartinib is a potent and selective type II FLT3 inhibitor that has been shown to elicit complete response (CR) or CR with incomplete recovery (CRi) in approximately 30% of patients with relapsed/refractory FLT3-ITD wild-type AML. As such, investigators hypothesized that the addition of quizartinib to standard 7+3 chemotherapy could improve survival in those with FLT3-ITD wild-type AML in the first line.
The multicenter, randomized, double-blind, placebo-controlled trial enrolled patients between the ages of 18 and 70 years with newly diagnosed FLT3-ITD–negative AML (ratio <.03) and an ECOG performance status below 3. FLT3-ITD was centrally screened through capillary electrophoresis and 7+3 chemotherapy was initiated during screening.
A total of 273 patients underwent induction therapy with 7+3 on days 1 through 7, followed by 60 mg/day of quizartinib or placebo on days 8 through 21. If subsequent response assessment revealed evidence of CR/CRi, patients proceeded to consolidation with 3 g/m2 of cytarabine over 12 hours on days 1, 3, and 5, plus quizartinib on days 6 through 19 for 1 to 4 cycles. Allogeneic transplant was sequenced next, if indicated, and followed by up to 12, 28-day cycles of maintenance therapy with quizartinib or placebo. In the case of partial response (PR) or resistant disease, patients underwent a second cycle of induction. If patients experienced CR/CRi to second induction, they were rerouted to consolidation and proceeded in the same sequence as the aforementioned population. Presence of PR or resistant disease prompted treatment discontinuation and study withdrawal.
EFS served as the primary end point. Secondary end points included OS, CR/CRi, and safety. Relapse-free survival (RFS) and duration of CR were evaluated as exploratory end points.
In the quizartinib arm, 180 patients started induction, 126 began consolidation, and 71 started treatment with single-agent quizartinib. In the placebo arm, 93 patients entered induction, 64 started consolidation, and 30 received placebo.
Regarding baseline characteristics, the median age was 57.1 years (range, 19-70) in the quizartinib arm vs 58.5 years (range, 21-70) in the placebo arm (P = .23); 41.1% and 44.1% of patients were 60 years of age or older, respectively (P = .63).
Most patients were male in both arms (quizartinib, 57%; placebo, 58%) compared with female (43% vs 42%; P = .89). ECOG performance status of 0, 1, and 2 was identified in 64%, 28%, and 8% of patients in the quizartinib arm, respectively, vs 61%, 33%, and 5% of patients in the placebo arm, respectively (P = .57). Most patients in the quizartinib arm had intermediate risk (45%) per European LeukemiaNet (ELN) 2017 criteria, followed by adverse (36%) and favorable (19%) risk, compared with 46% of patients who had adverse risk in the placebo arm, followed by favorable and intermediate risk (27% each; P = .01).
Represented mutational profiles, which were evaluated with centralized next-generation sequencing in the quizartinib and placebo arms, respectively, included FLT3-TKD (7% vs 6%; P = .80), NPM1 (23% vs 17%; P = .41), IDH1 (11% vs 9%; P = .59), IDH2 (18% vs 20%; P = .76), TP53 (11% vs 14%; P = .41), CBF-MYH11 (3% vs 3%; P = .37), and RUNX1-RUNXT1 (1% vs 2%; P = .29).
A total of 167 and 90 patients in the quizartinib and placebo arms were evaluable for response, respectively. After 1 cycle of induction therapy, 73% of patients achieved CR/CRi (CR, 53%; CRi, 20%) with quizartinib vs 71% (CR, 52%, CRi, 19%) with placebo (P = .74). PR, morphologic leukemia-free state, resistance, and death occurred in 11%, 2%, 12%, and 2% of patients on quizartinib, respectively, vs 9%, 0%, 12%, and 8% of patients on placebo. CR/CRi increased to 78% in both arms following 1 or 2 cycles of induction; CR/CRi with minimal residual disease negativity also increased from 42% to 44% with quizartinib and 40% to 43% with placebo.
A sensitivity analysis on OS according to age indicated improved survival regardless of whether patients were under the age of 60 years (HR, 0.595; 95% CI, 0.3470-1.021) or 60 years of age or older (HR, 0.552; 95% CI, 0.313-0.973). OS was also improved irrespective of whether patients underwent allogeneic hematopoietic cell transplant (HR, 0.610; 95% CI, 0.267-1.396) or not (HR, 0.567; 95% CI, 0.364-0.884).
However, when investigators stratified OS outcomes according to ELN2017 risk status, only patients with favorable (HR, 0.178; 95% CI, 0.038-0.841) and intermediate (HR, 0.353; 95% CI, 0.162-0.770) risk appeared to derive benefit from quizartinib. Patients with adverse risk derived no benefit from the addition of quizartinib to standard therapy (HR, 0.908; 95% CI, 0.554-1.487).
Additional results indicated that among patients who achieved CR/CRi, median RFS was NR with quizartinib vs 18.6 months with placebo (HR, 0.631; 95% CI, 0.414-0.962; P =.031).
Regarding safety, all-grade hematologic adverse effects (AEs) with quizartinib and placebo, respectively, included febrile neutropenia (37% vs 37%), decreased neutrophil count (27% vs 22%), decreased platelet count (28% vs 16%), and anemia (22% vs 16%). Non-hematologic AEs included fever (64% vs 67%), diarrhea (51% vs 40%), maculopapular rash (51% vs 40%), oral mucositis (36% vs 28%), lung infection (31% vs 33%), nausea (23% vs 27%), abdominal pain (26% vs 19%), fatigue (22% vs 19%), bacteremia (23% vs 16%), vomiting (23% vs 16%), and sepsis (14% vs 7%).
The most common cardiac events in the quizartinib arm were prolonged electrocardiogram QT corrected interval (12%), sinus tachycardia (7%), sinus bradycardia (4%), heart failure (2%), atrial fibrillation (1%), pericarditis (1%), and pericardial effusion (1%). In the placebo arm, the most common cardiac events were prolonged electrocardiogram QT corrected interval (11%), sinus tachycardia (3%), sinus bradycardia (2%), heart failure (2%), atrial fibrillation (2%), and supraventricular tachycardia (1%).
“Safety of quizartinib combined with intensive chemotherapy was generally manageable, with no new safety signals,” Montesinos reported.
Regarding QTcF interval, more patients experienced above a 30 ms increase from baseline in the quizartinib (37%) and placebo (25%) arms, vs above a 60 ms increase from baseline (21% vs 18%, respectively). Electrocardiogram data also revealed new ms above 450, 480, and 500 in 30%, 4%, and 4% of patients in the quizartinib arm, vs 19%, 8%, and 3% of patients in the placebo arm, respectively.
“A large biomarker plan to clarify underlying molecular mechanisms and final analyses with longer follow-up will be reported by the end of 2023,” Montesinos concluded.
Disclosures: Dr Montesinos reported research funding and consultant for Daiichi Sankyo.
Montesinos P, Rodríguez-Veiga R, Bergua Burgues JM, et al. Preliminary results of Quiwi: a double blinded, randomized clinical trial comparing standard chemotherapy plus quizartinib versus placebo in adult patients with newly diagnosed FLT3-ITD wild-type AML. Presented at: 2023 European Hematologic Association Congress; June 8-15, 2023; Frankfurt, Germany. Abstract S130.