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Gilteritinib: potent targeting of FLT3 mutations in AML
Mark Levis1, Alexander E Perl2
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; and.
Abstract:
Since the discovery of FMS-like tyrosine kinase-3 (FLT3)-activating mutations as genetic drivers in acute myeloid leukemia (AML), investigators have tried to develop tyrosine kinase inhibitors that could effectively target FLT3 and alter the disease trajectory. Giltertinib (formerly known as ASP2215) is a novel compound that entered the field late, but moved through the developmental process with remarkable speed. In many ways, this drug's rapid development was facilitated by the large body of knowledge gained over the years from efforts to develop other FLT3 inhibitors. Single-agent gilteritinib, a potent and selective oral FLT3 inhibitor, improved the survival of patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy. This continues to validate the approach of targeting FLT3 itself and establishes a new backbone for testing combination regimens. This review will frame the preclinical and clinical development of gilteritinib in the context of the lessons learned from its predecessors.
Insights
Gilteritinib, a potent FLT3 inhibitor, improved survival in patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations compared to chemotherapy. This validates targeting FLT3 and sets a new standard for AML treatment combinations.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Activating mutations in FMS-like tyrosine kinase-3 (FLT3) are key drivers in acute myeloid leukemia (AML).
- Development of tyrosine kinase inhibitors (TKIs) targeting FLT3 has been a focus for altering AML disease trajectory.
- Previous efforts to develop FLT3 inhibitors provided valuable knowledge for subsequent drug development.
Purpose of the Study:
- To review the preclinical and clinical development of gilteritinib (ASP2215) for FLT3-mutated AML.
- To contextualize gilteritinib's development within the framework of lessons learned from earlier FLT3 inhibitors.
- To highlight gilteritinib's efficacy as a single agent and its potential as a backbone for combination therapies.
Main Methods:
- Review of preclinical studies investigating gilteritinib's mechanism of action and potency.
- Analysis of clinical trial data evaluating gilteritinib's safety and efficacy in patients with relapsed or refractory AML.
- Comparative assessment of gilteritinib versus standard chemotherapy in a specific AML patient population.
Main Results:
- Gilteritinib demonstrated potent and selective inhibition of FLT3.
- Single-agent gilteritinib significantly improved survival in patients with relapsed/refractory FLT3-mutated AML compared to standard chemotherapy.
- The drug's rapid development was aided by prior research on FLT3 inhibitors.
Conclusions:
- Targeting FLT3 is a validated therapeutic strategy in AML.
- Gilteritinib represents a significant advancement, establishing a new standard of care for FLT3-mutated AML.
- Gilteritinib's success provides a foundation for exploring novel combination treatment regimens in AML.
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