S100: QUIZARTINIB PROLONGED SURVIVAL VS PLACEBO PLUS INTENSIVE INDUCTION AND CONSOLIDATION THERAPY FOLLOWED BY SINGLE-AGENT CONTINUATION IN PATIENTS AGED 18-75 YEARS WITH NEWLY DIAGNOSED FLT3-ITD+ AML

Background: Quizartinib (Quiz) is an oral, highly potent, and selective type II FLT3 inhibitor with single-agent activity in relapsed/refractory FLT3–internal tandem duplication positive (FLT3-ITD+) acute myeloid leukemia (AML). This is the first report of the global, randomized, double-blind, placebo (PBO)-controlled phase 3 QuANTUM-First trial (NCT02668653). Aims: QuANTUM-First aimed to determine if the addition of Quiz to standard induction (IND) and post remission (including allogeneic hematopoietic cell transplant [allo-HCT]) in first complete remission [CR1]) consolidation followed by single-agent continuation therapy for up to 3 years improved survival compared with chemotherapy alone in patients (pts) with newly diagnosed FLT3-ITD+ AML. Methods: Pts aged 18-75 y with newly diagnosed AML were centrally screened for FLT3-ITD prior to initiation of IND with cytarabine 100 mg/m2/day (200 mg/m2/day if institutional standard) for 7 days and anthracycline (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day) for 3 days. Pts at 193 sites in 26 countries who were FLT3-ITD+ provided informed consent and were randomized to Quiz (40 mg/day days 8-21) or PBO and were stratified by region (North America, Europe, and Asia/Other regions), age (<60 y, ≥60 y), and white blood cell count (<40×109/L, ≥40×109/L) at diagnosis. A second IND was allowed if residual AML was noted at the post-IND marrow exam. Pts who achieved CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/day) or PBO and/or allo-HCT followed by up to 3 y of continuation therapy with Quiz (30-60 mg/day) or PBO. The primary endpoint was overall survival (OS). Results: Between September 2016 and August 2019, 3468 pts were screened, and 539 pts with FLT3-ITD+ AML were randomized to Quiz (n=268) or PBO (n=271). The median age was 56 y (range, 20-75 y). Baseline pt and disease characteristics, including FLT3-ITD variant allele frequency, were balanced between the 2 arms. At data cutoff (August 2021), the median follow-up was 39.2 months and 58 pts remained on continuation therapy. OS was significantly longer in the Quiz arm than the PBO arm (hazard ratio [HR], 0.776; 95% CI, 0.615-0.979; 2-sided P=.0324). Median OS was 31.9 mo with Quiz vs 15.1 mo with PBO (Figure). CR/CRi rates were 71.6% and 64.9%, respectively. Allo-HCT in CR1 was performed in 157 pts (Quiz, 31%; PBO, 27%). When censored for allo-HCT, OS trended longer with Quiz vs PBO (HR, 0.752; 95% CI, 0.562-1.008; 2-sided P=0.055). Relapse-free survival was longer with Quiz than PBO (HR, 0.733; 95% CI, 0.554-0.969). Although rates of grade ≥3 adverse events (AEs) were similar across arms, grade ≥3 neutropenia was more frequent in the Quiz arm (18.1% vs 8.6%). Discontinuations due to AEs occurred in 20.4% of Quiz and 8.6% of PBO pts. A total of 56 treatment-emergent AEs were associated with a fatal outcome (Quiz, 11.3%; PBO, 9.7%), mostly due to infections. Grade 3/4 electrocardiogram QT prolonged occurred in 3.0% of Quiz vs 1.1% of PBO pts. Image:Summary/Conclusion: These pivotal findings show that the addition of Quiz to standard chemotherapy and up to 3 years of continuation therapy yielded statistically significant and clinically meaningful improvements to OS in adults with newly diagnosed FLT3-ITD+ AML up to age 75 y. The manageable safety profile further supports use of Quiz in combination with standard therapy, including allo-HCT, in FLT3-ITD+ AML.