Quizartinib Plus Chemotherapy Is Set to Be Evaluated in FLT3-ITD-Negative AML in Phase 3 Trial

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Following encouraging data from the phase 2 QUIWI trial (NCT04107727), investigators will examine the FLT3 inhibitor quizartinib (Vanflyta) in combination with chemotherapy for the treatment of patients newly diagnosed with FLT3-ITD–negative acute myeloid leukemia (AML) in the phase 3 QuANTUM-Wild study (NCT06578247).¹

“[Adding] a FLT3 inhibitor to intensive chemotherapy can improve the survival of patients with AML that harbors a FLT3-ITD or -TKD mutation,” Harry P. Erba, MD, PhD, said in an interview with OncLive. “The FLT3 receptor [also] plays an important role in normal hematopoiesis. When the FLT3 ligand binds to the extracellular domain of the FLT3 receptor, it causes dimerization of the receptor and activation of the intracellular tyrosine kinase, [setting off] a cascade of events leading to survival and proliferation of those cells. AML cells express the FLT3 receptor, and activation of this receptor can enhance leukemic survival and proliferation. Preclinical data show that the expression of FLT3 on the cell surface of blasts and the level of FLT3 ligand can be associated with prognosis in AML.”

Erba is a professor of medicine in the Department of Hematologic Malignancies and Cellular Therapy and a member of the Duke Cancer Institute at Duke Health in Durham, North Carolina.

In July 2023, the FDA approved quizartinib with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of patients with newly diagnosed AML that is FLT3-ITD positive.² The approval was based on data from the phase 3 QuANTUM-First trial (NCT02668653), which demonstrated that those who received quizartinib experienced a statistically significant and clinically meaningful improvement in overall survival (OS) vs those given chemotherapy plus placebo (HR, 0.78; 95% CI, 0.62-0.98; 2-sided P = .0324). However, accumulating data suggest the FLT3 inhibitor may have a larger role than originally hypothesized.

QUIWI Data Support Further Evaluation of Quizartinib/Chemotherapy Combination

QUIWI evaluated quizartinib in combination with chemotherapy in patients 18 to 70 years old with newly diagnosed FLT3-ITD–negative AML.³ Patients were randomly assigned 2:1 to receive quizartinib or placebo, both in combination with 7+3 chemotherapy. The primary end point was event-free survival (EFS), and OS was the key secondary end point.

Final results from QUIWI presented during the 2024 ASH Annual Meeting and Exposition showed that for patients who received quizartinib (n = 180) there was a 28% reduction in the risk of having an EFS event (n = 93; HR, 0.72; 95% CI, 0.53-1.0; 2-sided P = .0455). Patients in the quizartinib arm achieved higher 1-, 2-, 3-, and 4-year EFS rates than those in the placebo arm, at 58.3% vs 47.3%, 49.2% vs 36.6%, 44.6% vs 32.1%, and 44.6% vs 32.1%, respectively.

Patients in the quizartinib arm also experienced a 37% reduction in the risk of death compared with those in the placebo arm (HR, 0.63; 95% CI, 0.44-0.91; 2-sided P = .0121). The 4-year OS rates were 57.1% and 44.3% with quizartinib and placebo, respectively. The complete remission (CR)/CR with incomplete count recovery (CRi) rates after 2 cycles were 77.2% and 76.3%, respectively.

“A survival benefit was seen only in the patients with European LeukemiaNet 2017 [criteria] favorable- and intermediate-risk disease, not in patients with adverse-risk disease,” Erba commented. “Other subset analyses have shown the benefit was seen predominantly in patients with [an] NPM1 mutation. There is also a [FLT3] gene expression signature that has been used to identify patients who have a higher chance of benefit in terms of survival with the addition of quizartinib [to chemotherapy].”

Previous findings from a 2023 subgroup analysis of QUIWI showed that patients with a FLT3-like gene signature (n = 80) experienced a benefit in terms of EFS (HR, 0.45; 95% CI, 0.25-0.82; P = .009), OS (HR, 0.41; 95% CI, 0.20-0.84; P = .01), and relapse-free survival (RFS; HR, 0.37; 95% CI, 0.18-0.79; P = .01) in the quizartinib arm.⁴ Among patients without a FLT3-like gene signature, there were no significant differences between the 2 arms in terms of the total number of deaths, EFS, RFS, or OS.

Safety data from QUIWI revealed that 7 patients died during the first induction cycle in the quizartinib arm compared with 5 in the placebo group.³ Patients received allogeneic stem cell transplantation after first CR/CRi at rates of 32.2% and 30.1% in the quizartinib and placebo arms, respectively. The most common any-grade adverse effects (AEs) in the quizartinib group included febrile neutropenia (81%), rash (63%), and diarrhea (56%). In the placebo arm, common any-grade AEs included febrile neutropenia (78%), rash (60%), and mucositis (47%).

“There was no difference in early death rates between the 2 groups, including in patients over the age of 60 [years],” Erba noted. “The safety of quizartinib combined with intensive chemotherapy was felt to be manageable by investigators, [and] there were no new safety signals.”

Quizartinib Plus Chemotherapy Set for Phase 3 Study

In light of the encouraging results from QUIWI, QuANTUM-Wild was initiated to evaluate quizartinib in combination with chemotherapy in patients newly diagnosed with FLT3-ITD–negative AML (Figure).^1,5

Figure

The ongoing study is enrolling adult patients aged 18 to 70 years with an ECOG performance status of 0 to 2 who are receiving a standard 7+3 induction chemotherapy regimen. Prior leukapheresis, hydroxyurea for the treatment of hyperleukocytosis, cranial radiotherapy for central nervous system leukostasis, prophylactic intrathecal chemotherapy, and growth factor/cytokine support are the only prior treatments for AML permitted.

The study includes induction, consolidation, and maintenance phases.⁵ In the induction phase, all patients will receive a standard 7+3 chemotherapy regimen of cytarabine on days 1 to 7, an anthracycline on days 1 to 3, and quizartinib or placebo on days 8 to 21. Patients with a CR or CRi will enter the consolidation phase and receive high-dose cytarabine with quizartinib or placebo for 1 to 4 cycles, or 1 cycle followed by allogeneic hematopoietic stem cell transplant at the investigator’s discretion. Patients will then enter the maintenance phase to receive quizartinib or placebo.

Eligible patients will be randomly assigned 2:2:1 to receive quizartinib in all phases (arm A), quizartinib placebo in all phases (arm B), or quizartinib during induction and consolidation followed by placebo during the maintenance phase (arm C). Oral quizartinib will be administered at a dose of 60 mg per day for 14 days following the completion of chemotherapy in the induction and consolidation phases, except in patients who are also receiving concomitant strong CYP3A inhibitors—they will receive 30 mg of quizartinib.^1,5 In the maintenance phase, patients will receive quizartinib once daily for up to 36 cycles of 28 days. Those receiving placebo will have the same dosing schedule as quizartinib.

The primary end point is OS.¹ Secondary end points include EFS, duration of complete response, RFS, CR rate, CR with minimal or measurable residual disease negativity, and treatment-emergent AEs. All end points will be assessed in terms of arms A vs B.

In December 2024, Daiichi Sankyo announced that the first patient had been dosed in QuANTUM-Wild.⁶ The estimated target enrollment is 700 patients, and the estimated primary completion of the study is June 2030.¹

“This is an important area of investigation; FLT3 is ubiquitously expressed on AML blasts and appears to play an important role in the pathogenesis of the disease, even when there isn’t an ITD or TKD mutation,” Erba said. “Quizartinib is a potent inhibitor of FLT3 in its inactive confirmation [and] may improve the survival of patients, [including those without] this target. However, this benefit may [only] pertain to a specific subset of patients. No benefit was seen in patients with adverse-risk karyotype, where FLT3 potentially doesn’t play as important a role. There [also] appears to be an expression signature that will potentially allow us to identify patients who may benefit from the addition of quizartinib to intensive chemotherapy.”

References

1. Quizartinib or placebo plus chemotherapy in newly diagnosed patients with FLT3-ITD negative AML (QuANTUM-WILD). ClinicalTrials.gov. Updated February 19, 2025. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT06578247
2. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. News release. FDA. July 20, 2023. Accessed February 28, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia
3. Montesinos P, Rodriguez-Veiga R, Bergua Burgues JM, et al. Final results of QUIWI: a double blinded, randomized PETHEMA trial comparing standard chemotherapy plus quizartinib versus placebo in adult patients with newly diagnosed FLT3-ITD negative AML. Blood. 2024;144(suppl 1):1512. doi:10.1182/blood-2024-204779
4. Orgueira AM, Encinas MP, Diaz Arias JA, et al. The FLT3-like gene expression signature predicts response to quizartinib in wild-type FLT3 acute myeloid leukemia: an analysis of the PETHEMA QUIWI trial. Blood. 2023;142(suppl 1):974. doi:10.1182/blood-2023-180482
5. Montesinos P, Cheong JW, Daver N, et al. Trial in progress: the phase 3, randomized, double-blind, placebo-controlled QuANTUM-Wild study of quizartinib in combination with chemotherapy and as single-agent maintenance in newly diagnosed, FLT3-ITD-negative acute myeloid leukemia. Blood. 2024;144(suppl 1):1504.3. doi:10.1182/blood-2024-205101
6. QuANTUM-Wild phase 3 trial of Vanflyta initiated in patients with newly diagnosed FLT3-ITD negative AML. News release. Daiichi Sankyo. December 10, 2024. Accessed February 26, 2025. https://daiichisankyo.us/press-releases/-/article/quantum-wild-phase-3-trial-of-vanflyta-initiated-in-patients-with-newly-diagnosed-flt3-itd-negative-aml