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EHA 2022 | Results of QuANTUM-First: quizartinib vs placebo plus intensive chemotherapy in FLT3-ITD+ AML

Harry Erba, MD, PhD, Duke University, Durham, NC, discusses the rationale, design and results of QuANTUM-First (NCT02668653), a Phase III study comparing the efficacy of quizartinib vs placebo, both administered in combination with induction and consolidation chemotherapy in patients with FLT3-ITD+ acute myeloid leukemia (AML). The study met its primary endpoint of overall survival (OS) and showed that treatment with quizartinib was tolerable and significantly reduced relapse risk in patients up to 75 years old. This interview took place at the European Hematology Association (EHA) Congress 2022 held in Vienna, Austria.

Transcript (edited for clarity)

At the presidential session, I shared the results from the QuANTUM-First study, which was a clinical trial that evaluated the efficacy and safety of quizartinib, a type two second generation FLT3 inhibitor in patients with FLT3-ITD+ AML. FLT3 is the most commonly mutated gene in AML. One of the three most common. The most common of those mutations are the internal tandem duplication, ITD, which are associated with a worse prognosis due to a higher risk of relapse and worse overall survival...

At the presidential session, I shared the results from the QuANTUM-First study, which was a clinical trial that evaluated the efficacy and safety of quizartinib, a type two second generation FLT3 inhibitor in patients with FLT3-ITD+ AML. FLT3 is the most commonly mutated gene in AML. One of the three most common. The most common of those mutations are the internal tandem duplication, ITD, which are associated with a worse prognosis due to a higher risk of relapse and worse overall survival. The prognostic significance of the TKD mutation is much less certain. Now, we know from the RATIFY trial that the incorporation of a first generation type one inhibitor, midostaurin, into induction and consolidation chemotherapy improved the overall survival of patients with FLT3-mutated AML. In that study, they only allowed patients up to the age of 60. They allowed patients with both TKD and ITD mutation, and they gave continuation therapy, but only for a year and not after an allo-transplant. So in the QuANTUM-First study, we evaluated quizartinib for two weeks after chemotherapy induction or consolidation, versus placebo on the same single daily dose schedule. And then a continuation after consolidation or after allo-transplant of the same randomization of quizartinib versus placebo for up to three years. The patients were from all over the world. Very few from North America, because midostaurin had already been approved.

The primary endpoint of the study was improvement in overall survival. And the clinical trial met that endpoint. There was a statistically significant, and I believe clinically significant, improvement in the overall survival of patients with FLT3-ITD mutated AML, up to the age of 75. And it was 32 months with the addition of quizartinib to induction consolidation and continuation versus 15 months with placebo. The hazard ratio was 0.776 with a p-value of 0.03, with a two-sided log rank stratified analysis. That benefit was probably due to a lower risk of relapse that we observed. So relapse-free survival was superior in patients who received quizartinib. The cumulative incidence of relapse at two years was 31% versus 43% with placebo, and the duration of that first remission was three times as long with quizartinib than with placebo. So we believe that quizartinib decreases the risk of relapse in patients who’ve achieved a complete remission.

In terms of tolerability, there were a few more treatment emergent adverse events leading to fatalities with quizartinib than with placebo. It was 11.3% versus 9.7%. The 30 and 60-day mortality was slightly higher with the triple drug combination with quizartinib, but it was about 7.5% at 60 days versus 5% at 60 days with placebo. We did see QT prolongation. It was well managed, though. And in fact, only the instance of grade three QT prolongation was only 2.3% in our patients receiving quizartinib, and 0.7% in patients receiving placebo. So we believe that the safety profile of quizartinib with chemotherapy is acceptable. It’s manageable. There were no new safety signals. And the results showed that when we use a type two second generation, more potent, more specific FLT3 inhibitor, that we can improve the survival of patients up to the age of 75 with FLT3-ITD mutated AML when it’s used in combination with intensive chemo and continued for three years afterwards.

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Disclosures

Consultancy: Daiichi Sankyo, BMS