FDA Grants Quizartinib Priority Review for FLT3-ITD+ AML

Arnaud Lesegretain

The FDA has granted a priority review designation to a new drug application (NDA) for quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive acute myeloid leukemia (AML), according to Daiichi Sankyo, the manufacturer of the FLT3 inhibitor.

The priority designation, which follows a breakthrough therapy designation, is based on findings from the phase III QuANTUM-R study. Results from the trial presented at the 2018 EHA Congress showed that quizartinib reduced the risk of death by 24% compared with salvage chemotherapy in patients with FLT3-ITD—positive relapsed/refractory AML after first-line treatment with or without hematopoietic stem cell transplantation (HSCT).

At a median follow-up of 23.5 months, the median overall survival (OS) was 6.2 months (95% CI, 5.2-7.2) with quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).

Updated results are scheduled to be presented at the 2018 ASH Annual Meeting. Under the Prescription Drug User Fee Act, the FDA action date for a decision on the application is May 25, 2019.

"If approved, quizartinib has the potential to meaningfully advance treatment for patients with relapsed or refractory FLT3-ITD AML. Patients need more treatment options for this type of AML, which is particularly aggressive and difficult to treat. We are pleased that the FDA has filed our application for quizartinib for patients with relapsed or refractory FLT3-ITD AML, and granted priority review," Arnaud Lesegretain, Vice President, Oncology Research and Development and Head, AML Franchise, Daiichi Sankyo, said in a press release.

"Coupled with the recent acceptances of marketing applications for quizartinib in Japan and EU, we look forward to working with regulatory authorities in the U.S., Japan and EU to bring quizartinib to patients," added Lesegretain.

Data from the QuANTUM-R study (NCT02039726) confirmed the efficacy and safety of quizartinib that was observed in previous trials and showed the value of therapy targeting FLT3-ITD. It is the first trial to demonstrate improved OS for FLT3-ITD—associated AML patients who are treatment resistant or who relapsed after prior therapy.

FLT3-ITD is a common driver mutation that carries a poor prognosis, including a high risk of relapse, decreased response to salvage therapy, and poorer OS.

The investigational drug quizartinib is a small molecule receptor tyrosine kinase inhibitor targeting FLT3 that is administered orally once daily. FLT3 is a receptor tyrosine kinase that is commonly expressed in AML and is mutated in approximately 25% of AML patients.

QuANTUM-R enrolled patients 18 years or older with refractory AML or who had relapsed 6 months or less following complete remission (CR) after receiving standard AML therapies. The study allowed participation regardless of whether the patient had received stem cell transplantation; patients assigned to the quizartinib arm were allowed to resume this treatment following transplantation. However, patients receiving prior therapy with a FLT inhibitor except the multikinase inhibitor midostaurin (Rydapt), were excluded from the trial.

The primary endpoint in QuANTUM was OS in the intent-to-treat (ITT) population and secondary endpoints included objective response rate (ORR), and event-free survival (EFS) in the ITT population.

Patients were randomized 2:1 to once-daily quizartinib at 60 mg, with a 30-mg lead-in (n = 245) or to receive investigators’ choice of salvage chemotherapy that was selected prior to randomization. Chemotherapy choices included low-dose cytarabine (n = 29), the combination of mitoxantrone, etoposide, and cytarabine, (MEC; n = 40), or the combination of fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA; n = 53).

Patient characteristics in both arms were similar with a median age of 55 years for patients receiving quizartinib, and 57 years for those receiving chemotherapy. Of the quizartinib group, 33% of patients were refractory and 67% had relapses after an initial CR (CR1) of 6 months or less prior to the study. Thirty-four percent of patients in the chemotherapy group were refractory and 66% had relapsed after pre-study CR of 6 months or less.

Patients on quizartinib received a median drug exposure of 4 cycles (range, 1-43) whereas patients receiving salvage chemotherapy received a median of 1 cycle (range, 1-2).

The best response was composite CR (CRc) in 45% of patients with quizartinib and 27% with chemotherapy. Complete remission was achieved by 4% of patients, and 4% of patients had CR with incomplete platelet recovery. CR with incomplete blood count recovery (CRi) was reported for 40% of patients. Partial response (PR) was seen in 21% of quizartinib treated patients, which provided an ORR (CR + PR) of 69%. Twenty-five percent of patients showed no response and 5% of patients were not evaluated.

With salvage chemotherapy, the best response was CRc in 27% of patients comprising 1% CR, 0 CRp, and 25% CRi. Three percent of patients showed PR yielding an ORR of 30%. No response was observed in 37% of patients on salvage chemotherapy and 33% were not evaluated.

CRc was durable with quizartinib and lasted for 12 months (range, 10.4-27.1) versus 5 months (range, 3.5-12.6) with salvage chemotherapy. In the respective arms, 32% versus 12 % of patients proceeded to allo-HSCT transplantation.

Median EFS in the ITT population was 6.0 weeks with quizartinib versus 3.7 weeks with salvage chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; P = .107)

The treatment-emergent adverse event rates were comparable between the treatment arms and the quizartinib safety profile in this trial was consistent with the safety profiles reported in earlier phase II trials.

QTcF prolongation had been observed in earlier quizartinib trials. In QuANTUM, just 2 patients discontinued quizartinib due to prolonged QTcF. No torsades de pointes events were reported.

Applications for quizartinib in relapsed/refractory FLT3-ITD—positive AML are also under review in Europe and Japan.

Cortes J, Khaled S, Martinelli G, et al. Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication—mutated (MUT) relapsed/refractory AML in the phase 3, randomized, controlled QuANTUM-R trial. Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2600.