Quizartinib Plus Chemotherapy Shows Strong Activity in FLT3-ITD–Positive, NPM1-Mutated AML

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Patients with newly diagnosed FLT3-ITD–positive acute myeloid leukemia (AML) harboring an NPM1 mutation and epigenetic regulatory gene mutations derived a significant benefit with the addition of quizartinib (Vanflyta) plus standard chemotherapy vs placebo plus chemotherapy, according to data from an exploratory analysis of the phase 3 QuANTUM-First trial (NCT02668653) presented during the 2025 European Hematology Association Congress.1

Patients with FLT3-ITD–positive, NPM1-mutated disease who received quizartinib (n = 142) achieved a median overall survival (OS) that was not estimable (NE) compared with 15.1 months in the placebo arm (n = 140; HR, 0.64; 95% CI, 0.46-0.89). Those with FLT3-ITD–positive, DNMT3A-mutated disease experienced a median OS of 40.4 months and 9.6 months in the quizartinib (n = 112) and placebo (n = 113) arms, respectively (HR, 0.55; 95% CI, 0.39-0.78). Among patients with FLT3-ITD–positive, TET2-mutated disease, the median OS was NE in the quizartinib arm (n = 61) vs 11.3 months in the placebo arm (n = 67; HR, 0.60; 95% CI, 0.37-0.97). Notably, the median OS was NE among patients with FLT3-ITD–positive NPM1- and DNM3TA-mutated disease who received quizartinib (n = 86) vs 9.6 months in the placebo arm (n = 82; HR, 0.47; 95% CI, 0.31-0.71).

“Patients with the triple mutation of FLT3-ITD, NPM1, and DNMT3A particularly benefited from quizartinib, irrespective of age,” Mark J. Levis, MD, PhD, said during the presentation.

Levis is the program leader of the Hematologic Malignancies and Bone Marrow Transplant Program, as well as the director of the Adult Leukemia Service at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. He is also a professor of oncology, medicine, and pharmacology in the Division of Hematologic Malignancies at the Johns Hopkins University School of Medicine.

In July 2023, the FDA approved quizartinib in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as single-agent maintenance therapy following consolidation chemotherapy, in adult patients with newly diagnosed FLT3-ITD–positive AML.2 The regulatory decision was supported by prior data from QuANTUM-First.

Unpacking the Study Design and Baseline Characteristics

QuANTUM-First was a double-blind, randomized, global study that enrolled patients with newly diagnosed FLT3-ITD–positive AML.1,3 Patients were required to be 18 to 75 years old, have a FLT3-ITD allelic frequency of at least 3%, and an ECOG performance status of 0 to 2.3 All patients initiated 7+3 chemotherapy during screening.1 Random assignment was stratified by region (North America vs Europe vs Asia/other regions), age (<60 years vs ≥60 years), and white blood cell count (<40 × 109/L vs ≥40 × 109/L).

During the induction phase, all patients received cytarabine on days 1 through 7 plus daunorubicin or idarubicin on days 1 through 3, in combination with daily quizartinib at a dose of 35.4 mg on days 8 through 21 or placebo, for up to 2 cycles. Patients received high-dose cytarabine on days 1, 3, and 5 of the consolidation phase in combination with quizartinib or placebo on days 6 through 19, with or without allogeneic hematopoietic stem cell transplantation, for up to 4 cycles. Treatment was then continued with placebo or quizartinib at a starting dose of 26.5 mg which was increased to 53.0 mg once daily for up to 36 cycles.

The primary end point was OS. Secondary end points included composite complete remission (CRc) rate, event-free survival, complete remission rate, and safety.3

Baseline gene mutations were assessed by central laboratory testing via bone marrow and peripheral blood samples.1 The mutational statuses of 38 AML-related genes were analyzed using next-generation sequencing; a gene was classified as mutated if it displayed at least 1 somatic mutation with a minimum variant allele frequency of 2.7%. The study authors performed exploratory analyses to determine the effects of individual gene mutations on OS, CRc rate, and relapse-free survival.

At baseline, the most common mutations in the quizartinib arm were NPM1 (55%), DNMT3A (43%), and TET2 (24%). These mutations were reported at respective rates of 54%, 43%, and 26% in the placebo arm. The most common mutations in the quizartinib and placebo arms that were deemed by investigators to be prognostically relevant included RUNX1 (20% vs 24%), ASXL1 (15% vs 17%), and NRAS (10% vs 10%).

Notably, 96.5% (n = 500/518) of patients in the overall population had mutated disease. Comutations in NPM1 and DNMT3A were reported in 33.6% (n = 168/500) patients. Most patients (50.2%; n = 251/500) had an NPM1 mutation in combination with a mutation in DNMT3A, TET2, WT1, IDH1, or IDH2.

Further Efficacy Data

Additional findings revealed that the OS benefit with quizartinib vs placebo persisted in most of the individual mutational subgroups. No individual mutation fully favored the placebo arm compared with the quizartinib arm.

The OS HR for patients with any gene mutations related to myelodysplastic syndrome (MDS) was 0.998 (95% CI, 0.72-1.39). Investigators noted that small sample sizes and wide confidence intervals limited the interpretation of these findings. “There is much more to learn about the MDS mutations and their impact on this patient population,” Levis commented.

Notably, no individual baseline mutation appeared to lead to primary resistance to quizartinib. Patients with mutations in BCOR (odds ratio [OR], 7.80; 95% CI, 0.87-70.1), CEBPA (OR, 4.80; 95% CI, 1.12-20.6), and/or NRAS (OR, 3.46; 95% CI, 0.99-12.1) experienced the most significant CRc benefit with quizartinib vs placebo.

Patients in the placebo arm with FLT3-ITD–positive NPM1- and DNMT3A-mutated disease (n = 82) experienced a median OS of 9.6 months compared with 26.2 months among those with other mutations (n = 178; HR, 1.51; 95% CI, 1.08-2.10). Those with FLT3-ITD–positive NPM1- and DNMT3A-mutated disease also experienced an OS benefit with quizartinib vs placebo if they were less than 60 years old (HR, 0.32; 95% CI, 0.17-0.60) or at least 60 years old (HR, 0.67; 95% CI, 0.38-1.19). The median OS favored the quizartinib arm in patients with NPM1-mutated disease with an additional mutation in an epigenetic regulator (HR, 0.57; 95% CI, 0.40-0.81).

“[These data] speak to the need to wait for a mutational analysis before deciding which therapy to choose,” Levis said during his conclusion. “If [a patient] has this version of AML, they may benefit from intensive [chemotherapy] plus quizartinib.”

Disclosures: Levis disclosed industry affiliations with Astellas, Daiichi-Sankyo, BMS, GSK, Menarini, Novartis, Syndax, and Takeda.

References

1. Levis MJ, Montesinos P, Kim HJ, et al. The combination of a FLT3-ITD, NPM1mut and an epigenetic regulatory gene mutation confers unique sensitivity to quizartinib: analysis from the QuANTUM-First trial. Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract S140.
2. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. FDA. July 20, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia
3. Quizartinib with standard of care chemotherapy and as continuation therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First). ClinicalTrials.gov. Updated August 6, 2024. Accessed June 25, 2025. https://clinicaltrials.gov/study/NCT02668653