Quizartinib Bests Chemo for FLT3-Mutant AML

In a clinical first, a FLT3 inhibitor has demonstrated a survival benefit over chemotherapy in a phase III trial of patients with relapsed or refractory FLT3-mutant acute myeloid leukemia (AML).

The results, presented last month at the 23rd European Hematology Association Congress in Stockholm, Sweden, could help usher in a new standard of second-line treatment for this aggressive subtype of AML.

In the 367-person QuANTUM-R trial, patients who were refractory to or relapsed within 6 months of receiving first-line chemotherapy and then received quizartinib (Daiichi Sankyo) lived 6.2 months on average—1.5 months longer than those receiving a second chemotherapy regimen.

That's only a “modest improvement,” says Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. However, quizartinib is a more tolerable regimen, and “if I have a patient who's got relapsed AML with a FLT3 mutation,” Stein says, “based on the data presented, I'd reach for an oral agent with minimal toxicity like quizartinib before I'd reach for chemotherapy. It's just much easier on the patient.”

Mark Levis, MD, PhD, a lead trial investigator from Johns Hopkins University in Baltimore, MD, says he'd be “thrilled” if quizartinib earns approval as a second-line therapy based on the results. However, “these are not the patients I want to be treating” with the drug, he says. “It's got to be moved up front. That's where we're going to see the real benefit, I believe.” The ongoing QuANTUM-First trial is comparing quizartinib with placebo, both as add-ons to chemotherapy, in newly diagnosed patients.

Currently, the only FLT3 inhibitor approved for use in the 25% to 30% of patients with AML who harbor a FLT3 mutation is the multikinase inhibitor midostaurin (Rydapt; Novartis). “It's a good drug,” says Amir Fathi, MD, of Massachusetts General Hospital in Boston, MA, but “it's nonselective.” Midostaurin demonstrated only modest clinical benefit in single-agent trials, but it did offer a survival advantage when given with chemotherapy as a first-line treatment—extending 4-year survival rates from about 44% to 51%.

That's the benchmark for quizartinib in QuANTUM-First, as well as for two other FLT3 inhibitors now in phase III trials: gilteritinib (Astellas Pharma) and crenolanib (AROG Pharmaceuticals).

All three are more selective and potent than midostaurin, with quizartinib being the strongest. In fact, quizartinib is so potent that it seems to inhibit even wild-type FLT3, according to phase II trial results published in May.

Among patients with FLT3-mutant disease, however, quizartinib is thought to work only against internal tandem duplications (ITD). Patients with tyrosine kinase domain (TKD) substitutions, the less common of the two main types of FLT3 alterations, would need gilteritinib or crenolanib. Both of those drugs broadly inhibit ITD and TKD mutations.

The FDA has set a November decision date regarding gilteritinib's approval as a monotherapy for relapsed or refractory disease. According to Levis, the drug met its co-primary endpoint in the phase III ADMIRAL trial, besting chemotherapy in the percentage of patients achieving complete remission with either full or partial hematologic recovery. With the trial ongoing, it's not known yet whether gilteritinib will improve overall survival—and the FDA may want that data prior to granting approval. –Elie Dolgin