According to findings from the phase III QuANTUM-R study, overall survival was improved with quizartinib compared with chemotherapy in patients with <em>FLT3</em>-ITD–positive relapsed/refractory acute myeloid leukemia after first-line treatment with or without hematopoietic stem cell transplantation.<br />
Antoine Yver, MD, MSc
According to findings from the phase III QuANTUM-R study, overall survival (OS) was improved with quizartinib compared with chemotherapy in patients withFLT3-ITDpositive relapsed/refractory acute myeloid leukemia (AML) after first-line treatment with or without hematopoietic stem cell transplantation (HSCT).
According to Daiichi Sankyo, the manufacturer of the FLT3 inhibitor, specific data from the pivotal quizartinib trial will be presented at an upcoming oncology conference. 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 withFLT3-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 withFLT3-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 theJournal of Clinical Oncologyfrom a phase I study that examined quizartinib in 76 patients with relapsed/refractory AML, irrespective ofFLT3-ITD mutation status. Among 17FLT3-ITDpositive 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 theFLT3-ITDpositive group included 1 CR, 1 CRp, 2 CRis, and 5 PRs. There were 5 (14%) responses among the 37FLT3-ITDnegative patients, including 2 CRps and 3 PRs. Among the remains 22 patients who were not tested or had an indeterminateFLT3-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-diagnosedFLT3-ITDpositive 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 diagnosedFLT3-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 withFLT3mutationpositive 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.