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

Jorge Cortes, MD

Quizartinib reduced the risk of death by 24% compared with salvage 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 presented at the 2018 European Hematology Association (EHA) Congress.

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).

“Single-agent quizartinib significantly prolonged overall survival in patients with R/R FLT3-ITD—mutated AML compared with salvage chemotherapy,” said lead QUANTUM-R author Jorge Cortes MD, deputy chair and professor in the Leukemia Department of The University of Texas MD Anderson Cancer Center.

“Our findings demonstrated that patients on quizartinib alone had an estimated overall survival of 27% after 52 weeks of treatment compared to 20% for patients on salvage chemotherapies,” said Cortes.

Data from the QuANTUM-R study (NCT02039726) presented by Cortes 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.

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.

At EHA, Cortes presented findings from the global, phase III, randomized, controlled QuANTUM-R trial on behalf of a large international research team.

“Currently, there are no approved targeted therapies for patients with relapsed FLT3-ITD—associated AML, which represents a significant unmet medical need,” said Cortes.

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.

“Over the course of the development program, quizartinib has demonstrated safety in over 2500 patients,” said Cortes.

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.

“These pivotal data confirm that targeting FLT3-IT with this potent new therapy may be of significant clinical value,” said Cortes. “These results represent the first positive phase III trial to demonstrate improved overall survival in patients with AML-associated FLT3-ITD.”

Responding to an audience question, Cortes said, “Allele frequency made no difference in the efficacy of quizartinib; actually, an earlier phase II study enrolled patients with no FLT3-ITD—mutation who had a 30% response rate. We are still investigating this response but it suggests the possibility that quizartinib may have activity in some patients without this mutation.”

Cortes said that the next step was the ongoing phase III QuANTUM-First trial (NCT02668653) of standard chemotherapy with and without quizartinib in patients with newly diagnosed FLT3-ITD—mutated AML.

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.

<<< 2018 European Hematology Association Congress

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.