Quizartinib Improves Survival in FLT3-ITD+ Relapsed/Refractory AML

Antoine Yver, MD, MSc

Quizartinib improved overall survival (OS) compared with chemotherapy in patients with FLT3-ITD—positive relapsed/refractory acute myeloid leukemia (AML) after first-line treatment with or without hematopoietic stem cell transplantation (HSCT), according to findings from the phase III QuANTUM-R study.

Specific data from the pivotal quizartinib trial will be presented at an upcoming oncology conference, according to Daiichi Sankyo, the manufacturer of the FLT3 inhibitor. The company noted in a press release that the safety profile for quizartinib in the QuANTUM-R trial was similar to adverse event (AE) reports for similar doses in other studies.

“Single-agent quizartinib is the first FLT3 inhibitor to show a significant improvement in overall survival compared to cytotoxic chemotherapy in a randomized phase III study of patients with relapsed/refractory AML with FLT3-ITD mutations, a very aggressive form of the disease with limited treatment options,” Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development, Daiichi Sankyo.

“We sincerely thank all of the investigators and patients who participated in this study and will share the results of the QuANTUM-R study at an upcoming medical meeting. We look forward to working with regulatory authorities worldwide to potentially bring quizartinib to patients as quickly as possible,” added Yver.

The global, open-label phase III QuANTUM-R included 367 patients with FLT3-ITD-mutated relapsed/refractory AML. Patients had received standard frontline AML treatment with or without HSCT, and their duration of remission was ≤6 months. The trial randomized patients in a 2:1 ratio to single-agent quizartinib or chemotherapy. OS was the primary endpoint.

Results were previously published in the Journal of Clinical Oncology from a phase I study that examined quizartinib in 76 patients with relapsed/refractory AML, irrespective of FLT3-ITD mutation status. Among 17 FLT3-ITD—positive patients, the overall response rate was 53% (n = 9).

The median age of the patients on the trial was 60 years (range, 23-86) and the median number of prior therapies was 3 (range, 0-12). Escalating quizartinib doses of 12 to 450 mg orally were administered daily.

Overall, 23 (30%) of 76 patients achieved a response, including 2 complete remissions (CRs), 3 CRs with incomplete platelet recovery (CRp), 5 CRs with incomplete hematologic recovery (CRi), and 13 partial remissions (PRs). The median OS was 14.0 weeks and the median duration of response was 13.3 weeks.

The 9 responses in the FLT3-ITD—positive group included 1 CR, 1 CRp, 2 CRis, and 5 PRs. There were 5 (14%) responses among the 37 FLT3-ITD—negative patients, including 2 CRps and 3 PRs. Among the remains 22 patients who were not tested or had an indeterminate FLT3-ITD status, the response rate was 41%, comprising 1 CR, 3 CRis, and 5 PRs.

Grade 3 QT prolongation was the dose-limiting toxicity, with the maximum-tolerated dose determined to be 200 mg/day. Adverse events related to quizartinib that occurred in at least 10% of patients included nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%). Most AEs were grade 2.

Quizartinib is also being explored in the phase III QuANTUM-First study, which is examining the FLT3 inhibitor in patients with newly-diagnosed FLT3-ITD—positive AML. Patients on the trial are randomized to quizartinib plus standard chemotherapy followed by maintenance quizartinib, or placebo plus standard chemotherapy followed by maintenance placebo.

In April 2017, the FDA approved midostaurin (Rydapt)—which inhibits multiple kinases, including FLT3—for the treatment of adult patients with newly diagnosed FLT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

A new drug application was recently filed with the FDA by Astellas Pharma for the FLT3 inhibitor gilteritinib for the treatment of adult patients with FLT3 mutation—positive relapsed or refractory AML.

Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.