Quizartinib ups survival over salvage chemo in FLT3-ITD+ AML
The selective FLT3* inhibitor quizartinib significantly improves survival compared with salvage chemotherapy in patients with relapsed/refractory acute myeloid leukaemia (AML) and FLT3-internal tandem duplication (ITD), regardless of prior haematopoietic stem cell transplantation (HSCT), reveals the QuANTUM-R** study presented at EHA 2018.
FLT3-ITD, a common driver mutation in AML, is associated with a poor prognosis, including decreased response to salvage therapy, high relapse risk, and poorer overall survival (OS).
“Currently, there are no approved targeted therapies for patients with relapsed FLT3-ITD–associated AML, which represents a significant unmet medical need,” said Dr Jorge Cortes of The University of Texas MD Anderson Cancer Center in Houston, Texas, US.
After a median follow-up of almost 2 years (23.5 months), survival was prolonged with quizartinib vs salvage therapy (median OS, 6.2 vs 4.7 months, hazard ratio [HR], 0.76; one-sided p=0.0177). The estimated survival rate at 1 year was 27 percent vs 20 percent for the quizartinib and the salvage chemotherapy arms, respectively. [EHA 2018, abstract LB2600]
The global, phase III QuANTUM-R trial randomized 367 patients with FLT3-ITD─positive AML, with or without HSCT, in a 2:1 ratio to receive oral quizartinib 60 mg (30 mg lead-in) or the investigator’s choice of salvage chemotherapy. The salvage therapies allowed included low-dose cytarabine; cytarabine, fludarabine, and granulocyte-colony stimulating factor with idarubicin; or etoposide, mitoxantrone, and intermediate-dose cytarabine.
The secondary endpoint of event-free survival trended in favour of quizartinib compared with salvage chemotherapy (6.0 vs 3.7 weeks, HR, 0.90; p=0.107), although the difference between groups did not reach statistical significance.
Comparable treatment-emergent adverse event rates were observed for both treatment arms. In particular, the safety profile of quizartinib was consistent with that seen in previous phase II trials. Two patients discontinued quizartinib because of QTcF prolongation. There were no reports of torsades de pointes.
“These pivotal data confirm the efficacy and safety of quizartinib and the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor,” said Cortes.
Quizartinib is a highly potent and selective small molecule inhibitor targeting the FLT3, a receptor tyrosine kinase mutated in about a quarter of AML patients, according to the researchers. Monotherapy treatment with the once-daily oral inhibitor has been shown to have promising antileukaemic activity in previous phase II trials.
“These results represent the first positive phase III trial to demonstrate improved OS with FLT3 inhibitor in the relapsed/refractory FLT3-ITD–positive AML setting,” said Cortes.
A phase III study investigating the effect of adding on quizartinib to standard chemotherapy on newly diagnosed FLT3-ITD–positive AML is currently ongoing.