Future directions for FLT3 inhibitors in AML treatment

The AML Hub was pleased to speak with Eytan Stein, Memorial Sloan Kettering Cancer Center, New York, US. We asked, What might the future hold for the evolution of FLT3 inhibitors in the treatment of AML?

Stein summarizes the approved indications for currently available FLT3 inhibitors and considers potential future directions for their investigation in the treatment of acute myeloid leukemia (AML), including in combination regimens and in patients with FLT3-ITD-negative AML.

Key points

• There are currently three FLT3 inhibitors approved by the U.S. Food and Drug Administration (FDA) for the treatment of AML:
  • Quizartinib, approved for patients with newly diagnosed (ND) FLT3-internal tandem duplication (FLT3-ITD) AML, in combination with standard induction and consolidation, and as maintenance monotherapy following consolidation chemotherapy.¹
  • Midostaurin, approved for patients with ND FLT3-mutated (FLT3m) AML, in combination with standard induction and consolidation chemotherapy.²
  • Gilteritinib, approved as monotherapy for patients with relapsed or refractory (R/R) FLT3m AML.³
• One key area of interest is the investigation of FLT3 inhibitors in combination with azacitidine (Aza) + venetoclax (Ven), in older patients with FLT3m AML.
  • A phase I/II trial (NCT04140487) of the triplet regimen gilteritinib + Aza + Ven showed favorable survival and durable response rates in patients with ND FLT3m AML who were unfit for intensive chemotherapy.⁴
  • A phase I/II trial (NCT03661307) investigating quizartinib + Ven + decitabine also demonstrated promising remission and survival rates in both ND and R/R FLT3m populations.⁵
• Another focus is the use of FLT3 inhibitors alongside other targeted therapies, in patients with R/R AML and concomitant mutations such as IDH1 or NPM1 mutations.
• The potential role of FLT3 inhibitors in patients with AML without FLT3 mutations is also being explored.
  • In the phase II QUIWI trial (NCT04107727), the addition of quizartinib to chemotherapy demonstrated prolonged event-free survival and overall survival vs chemotherapy alone, in patients with ND FLT3-ITD-negative AML.⁶
  • The effects of quizartinib vs placebo will be further investigated in this population in the phase III QuANTUM-WILD trial (NCT06578247).⁷

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