Quizartinib bounces back, doubles OS in FLT3-ITD-positive AML

The oral FLT3 inhibitor quizartinib more than doubled overall survival (OS) when added to first-line chemotherapy in patients with newly diagnosed FLT3-ITD*-positive acute myeloid leukaemia (AML) in the phase III QuANTUM-First** trial.

Compared with chemotherapy alone, quizartinib plus chemotherapy reduced the risk of death by 22.4 percent. At more than 39 months of follow-up, the primary endpoint of median OS was almost 32 months with the quizartinib arm vs 15 months with the chemo arm.

The positive topline results give quizartinib a good chance of winning US FDA nod for newly diagnosed AML, following its rejection in June 2019 for previously treated AML. Among the reasons cited by the agency then were the modest survival results, lack of robust data, high proportion of randomly assigned but untreated patients, and the risk of QT prolongation with the drug.

Then came the latest data – quizartinib and chemotherapy regimen allowed patients with newly diagnosed FLT3-ITD*-positive AML  to live longer vs chemo alone. [EHA 2022, abstract S100] Experts said this paves the way for regulatory filings for quizartinib.

A new standard of care?

“With no new safety signals identified, the results have the potential to change the standard of care for adult patients with newly diagnosed FLT3-ITD-positive AML,” said principal investigator Dr Harry Erba of Duke Cancer Institute in Durham, North Carolina, US at EHA 2022.

Dr António Almeida, EHA president-elect, and department head at Hospital da Luz, Lisbon, Portugal, agreed, saying the results suggest “a new treatment option” for a difficult-to-treat subset of AML. “Patients with FLT3-ITD-positive AML represent a particularly poor prognostic group who, despite the availability of FLT3 inhibitor midostaurin, still have an unmet need for more treatments.”

According to the American Cancer Society, the 5-year survival rate for adults with AML is only 24 percent. About 1 in 4 newly diagnosed patients carry the FLT3-ITD mutation, which has shorter survival and a higher risk of relapse.

Evidence for quizartinib

In an earlier phase III QuANTUM-R trial, quizartinib, given as a single agent, had a survival benefit vs salvage chemotherapy. More impressively, this was in the setting of relapsed/refractory FLT3-ITD-positive AML. [Lancet Oncol 2019;20:984-997] The current QuANTUM-First trial further looked into quizartinib efficacy when added to induction chemotherapy –  and over the long term – in patients with FLT3-ITD-positive AML. Patients (median age 56 years) were randomly assigned to oral quizartinib 40 mg once daily (n=268) on days 8–21 or placebo (n=271) after induction chemotherapy.

At a median follow-up of 39.2 months, 58 patients remained on treatment. The quizartinib group had a significantly better OS (p=0.032). Relapse-free survival was also longer with quizartinib, particularly in patients who achieved remission (39.3 months vs 13.6 months for placebo).

“Grade 3 or higher neutropenia was more frequent with quizartinib. Also, more patients discontinued treatment because of adverse events,” said Erba.

Overall, 56 treatment-emergent adverse events were associated with a fatal outcome in both groups, which Erba attributed to infections. “Prophylactic antifungal and antibacterial antibiotics were the recommended interventions, data of which are not yet available at this time.”

As most relapses of AML with FLT3-ITD-mutation occur within 3 years of achieving remission, he said continuing with quizartinib for up to 36 cycles, or about 3 years, is recommended.