Second-Generation FLT3 Inhibitors Produce Higher Response Rates in AML

Naval G. Daver, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discusses how the efficacy compares between first- and second-generation FLT3 inhibitors in acute myeloid leukemia (AML).

The first-generation agents entered the treatment landscape of AML about 15 years ago, and these included lestaurtinib, midostaurin (Rydapt), sorafenib (Nexavar), and sunitinib (Sutent). These were not developed as FLT3 inhibitors, Daver says, and were referred to as re-purposed FLT3 inhibitors. They were developed to target other pathways, but researchers later discovered that they were multikinase inhibitors that also inhibited the FLT3 kinase. Researchers also realized thatFLT3was associated with an adverse prognosis.

Second-generation inhibitors, such as gilteritinib (Xospata), quizartinib, and crenolanib, were developed to specifically target FLT3. Although they did have other targets, Daver says these agents were developed to be a very potent class of FLT3 inhibitors.

In single-agent studies, the first-generation agents induced response rates of around 5% to 10% in patients with relapsed/refractoryFLT3-mutant AML. Although these responses were modest, the agents worked better in combination with either azacitidine or induction therapy.