QUIWI: FLT3 type II inhibitor confers survival advantage in acute myeloid leukaemia

The FLT3 type II inhibitor quizartinib, when combined with induction and consolidated therapy and continued for up to 12 cycles, yields survival benefits such as prolonged overall and relapse-free survival in patients with newly diagnosed wild-type acute myeloid leukaemia (AML), as shown in the interim results of the phase II study QUIWI.

Over a median follow-up of 17 months, fewer quizartinib-treated than placebo-treated patients had events (n=92/180 vs n=60/93). In line with this, the primary endpoint of event-free survival (EFS) was longer with quizartinib, although the difference was not significant (16.5 vs 10.6 months; hazard ratio [HR], 0.741, 95 percent confidence interval [CI], 0.535–1.026; p=0.059), reported Dr Pau Montesinos of La Fe University and Polytechnic Hospital, Valencia, Spain, who spoke to an audience at EHA 2023.

However, looking at other endpoints, Montesinos noted the superiority of quizartinib over placebo.

The number of deaths was lower in the quizartinib arm (n=56/180 vs n=46/93), translating to an extended median overall survival relative to the placebo arm (not reached vs 20.2 months; HR, 0.569, 95 percent CI, 0.385–0.841; p=0.004). The same was true for relapse-free survival (not reached vs 18.6 months; HR, 0.631, 95 percent CI, 0.414–0.962; p=0.031), with fewer quizartinib-patients experiencing relapse (n=56/131 vs n=38/70). [EHA 2023, abstract S130]

These results were consistent with that of a sensitivity analysis, according to Montesinos, wherein add-on quizartinib was associated with prolonged overall survival benefit in subgroups defined by age (<60 years: HR, 0.595; ≥60 years: HR, 0.552), receipt of allogeneic hematopoietic stem cell transplantation (allo-SCT; yes: HR, 0.610; no: HR, 0.567), and European LeukemiaNet (ELN) 2017 risk stratification (favourable risk: HR, 0.178; intermediate risk: HR, 0.353).

However, patients in the ELN2017 adverse risk group do not benefit from additional quizartinib therapy (HR, 0.908), Montesinos pointed out.

As for safety, the frequency of haematologic (ie, febrile neutropenia) and nonhaematologic (ie, fever, lung infection, bacteraemia, and sepsis) were similar in the quizartinib and placebo arms.

“The safety of quizartinib combined with intensive chemotherapy was generally manageable, with no safety signals,” Montesinos said.

Study details

QUIWI was conducted in phases. First was the double-blinded phase, wherein the patients were randomly assigned to receive cytarabine 200 mg/m² (days 1-7) and idarubicin 12 mg/m² (days 1-3) plus either quizartinib 60 mg/day or placebo for 14 days, with stratification by age (<60 vs ≥60 years) at diagnosis. For patients who did not achieve response (complete remission or complete remission with incomplete recovery), a second identical induction cycle.

Then, a consolidation phase was initiated (up to 4 cycles), wherein the patients received high-dose cytarabine on days 1, 3, and 5 plus quizartinib or placebo for 14 days. Those with high genetic risk or intermediate risk with minimal residual disease positivity were recommended for allo-SCT. A 12-cycle maintenance phase with 60-mg quizartinib or placebo was conducted after the consolidation phase or after allo-SCT.  

The study population included adult patients with newly diagnosed FLT3-ITD wild-type AML and who were fit for intensive chemotherapy. A total of 273 patients (median age 57 years, 57.5 percent men) entered the induction phase, 190 entered the consolidation phase, and 101 entered the continuation phase.

Response rates after one or two induction cycles did not differ between the quizartinib and placebo arms (78 percent in both).

“If confirmed, the QUIWI trial results may lead to novel curative approaches for adult patients with newly diagnosed FLT2-ITD negative AML,” Montesinos said.

“A large biomarker plan to clarify underlying molecular mechanisms and final analyses with longer follow-up will be reported by the end of 2023,” he added.