Final Results of Quiwi: A Double Blinded, Randomized Pethema Trial Comparing Standard Chemotherapy Plus Quizartinib Versus Placebo in Adult Patients with Newly Diagnosed <i>FLT3</i>-ITD Negative AML

Background: Inhibition of FLT3 and other kinases through oral targeted agents could improve standard chemotherapy outcomes for fit AML FLT3-ITD negative patients. The randomized SORAML trial from the SAL group, including all genetic subtypes, showed that the addition of type II inhibitor sorafenib improved leukemia-free, but not overall survival (OS) among newly diagnosed fit AML patients. Quizartinib (Quiz) is a potent type II inhibitor showing about 30% of complete remissions (CR) and CR with incomplete recovery (CRi) as monotherapy for relapsed/refractory FLT3-ITD negative AML. With this rationale, the PETHEMA group designed a randomized, double-blind, placebo (PBO)-controlled phase II QUIWI trial (NCT04107727), with interim preplanned analyses (data cut-off March 2023) reporting 2-years overall survival (OS) 63.5% with Quiz vs. 47% with PBO (p=0.004). Here, we report the final analyses of the QUIWI trial with significantly prolonged follow-up (data cut-off July 26th, 2024) and full data-base cleaning. Methods: Multicenter, randomized, PBO-controlled, double-blinded phase II clinical trial. Patients with newly diagnosed FLT3-ITD negative AML, aged 18 to 70 years, and fit for intensive chemotherapy were centrally screened for FLT3-ITD prior to randomization. The trial was conducted in two phases: an open-label safety run-in phase exploring Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3), and Quiz 60 mg/d x 14 days to establish the dose for the randomized phase. The double-blinded phase 2:1 used randomization stratified by age (&amp;lt;60 vs. ≥60 years old) at diagnosis. A second identical induction cycle was allowed in case of failure to achieve CR/CRi after the first cycle. Consolidation (up to 4 cycles) consisted of high dose Cytarabine on Days 1, 3, and 5 plus Quiz or PBO for 14 days. Patients with high genetic risk or intermediate with MRD positivity were recommended for allo-SCT. A 12 cycles maintenance phase with 60 mg Quiz or PBO started after the consolidation or after allo-SCT. MRD monitoring, was performed through the PETHEMA centralized platform (PLATAFO-LMA). NPM1 and CBF patients was assessed for MRD using RT-qPCR standardized techniques, and the remaining subgroups by standardized multiparametric flow cytometry. The primary objective of QUIWI trial was to compare the event-free survival (EFS) (failure to achieve CR/CRi after 1 or 2 cycles, death in CR/CRi, or relapse, whichever occurs the first) between Quiz and PBO arms. OS was a key secondary endpoint. A blinded independent review committee (IRC) revised response assessment and European Leukemia Net (ELN) risk classification (2017 and 2022), among other critical parameters. Analyses were performed on an intent-to-treat basis. Results: From September 2019 to November 2021, 284 Pts were enrolled in 45 Spanish PETHEMA centers, 11 of them were included in the safety run-in phase establishing 60 mg/day of Quiz for the randomized phase. 273 Pts were randomized to Quiz (n=180) or PBO (n=93). The median age was 57 y [IQR, 48 - 64 y]. Baseline pts and disease characteristics were balanced between the 2 arms (ELN 2022 risk distribution for Quiz and PBO was low 29.4% vs. 25.8%, intermediate 12.8% vs. 13.9%, and high 57.8% vs. 60.2%, p=0.8). The median follow-up was 39.4 months. Median EFS was 18.8 mo with Quiz vs. 9.9 mo with PBO (hazard ratio [HR], 0.732; 95% CI, 0.533-1.005; 2-sided P=0.053). Regarding OS, 71 out of 180 patients died in the Quiz arm, and 51 out of 93 in the PBO. Median OS was not reached with Quiz vs 29.3 mo with PBO (HR, 0.625; 95% CI, 0.436-0.897; P=0.009), and the 3-years OS was 61% with Quiz vs. 46% with PBO. Quiz benefit was observed among both &amp;lt;60 vs. ≥60 years old pts (HR, 0.63, P=0.067; and HR, 0.63, P=0.085, respectively), and among allo-SCT and no allo-SCT pts (HR, 0.59; P=0.16; and HR, 0.64; P=0.03, respectively). CR/CRi rate after 2 cycles was 77.2% in the Quiz arm and 76.3% in the PBO. Death during first induction cycle was 7 (4%) for Quiz and 5 (5%) for PBO. Overall, 86 (31.5%) pts received an allo-SCT after first CR/CRi, 58 (32.2%) in Quiz and 28 (30.1%) in PBO arm. Maintenance therapy started in 102 (37%) pts, 72 (40%) in Quiz and 30 (32%) in PBO arm. No new safety signals were observed among Quiz and PBO arms. Conclusion: Our study strongly suggests that the addition of Quiz to 3+7 may prolong OS in newly diagnosed FLT3-ITD negative AML. A large global phase III randomized trial (Quantum-WT) will aim to confirm the PETHEMA-QUIWI results.