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ATLANTA -- Patients with relapsed or refractory FLT3-mutated acute myelogenous leukemia (AML) lived significantly longer if they received the novel FLT inhibitor gilteritinib (Xospata) instead of salvage chemotherapy, according to an updated analysis of a randomized trial.

Treatment with gilteritinib led to a median overall survival (OS) of 9.3 months as compared with 5.6 months for patients who received conventional chemotherapy. Twice as many gilteritinib-treated patients were alive at 12 months.

Objective responses occurred in more than twice as many patients in the gilteritinib group, and the median duration of response was almost a year, reported Alexander E. Perl, MD, of the Abramson Cancer Center and University of Pennsylvania in Philadelphia, at the American Association for Cancer Research (AACR) annual meeting.

"This [represents] a major change in how we approach patients in the relapsed-and-refractory setting, because now we're using molecularly targeted therapy to select patients who can benefit from this approach," Perl said during an AACR press briefing. "We've shown that a lower-toxicity agent, more or less comparable to the low-intensity approaches, can outperform the general fallback of using standard toxic chemotherapy that requires an inpatient hospital stay. This is a practice-changing result, and we think establishes a new standard of care for this population."

Louis Weiner, MD, of Georgetown University and the Lombardi Comprehensive Cancer Center in Washington, was impressed by the results and agreed with Perl's conclusions about the trial's impact on clinical practice.

"This is a new, practice-changing strategy that is something we've been needing in the field of acute myelogenous leukemia in the entire time I have been an oncologist," said Weiner. "To have something like this is really special."

In as many as 70% of patients, AML relapses after initial remission with induction chemotherapy, the standard first-line approach to treatment. Additionally, as many as 40% of patients with AML have disease that is refractory to induction chemotherapy. Relapsed/refractory AML responds poorly to salvage chemotherapy and has a poor prognosis, including short survival, Perl noted.

FLT3 mutations occur in about 30% of AML cases, including the FLT3 internal tandem duplication (ITD) mutations, which confer an increased risk of early relapse and are associated with poor survival. Midostaurin (Rydapt), a first-generation FLT3 inhibitor achieves variable inhibition of FLT3 in vivo, but has been shown to improve survival in combination with intensive chemotherapy for patients with newly diagnosed FLT3-mutated AML, Perl continued. As single-agent therapy, midostaurin did not induce complete remissions in relapsed/refractory AML.

Quizartinib (expected to be approved in the near future) and sorafenib (Nexavar) have more potent inhibition of FLT3, and have demonstrated significant clinical activity alone or in combination with chemotherapy. However, both agents have brief response durations because of treatment-emergent tyrosine kinase domain (TKD) D835 resistance mutations, said Perl.

Gilteritinib, which received in late 2018, has activity against FLT3-ITD and FLT3-TKD D835 mutations, as well as greater specificity for FLT3 as compared with other agents in the class. The drug exhibited activity in patients with FLT3-mutated AML and demonstrated good tolerance across a wide range of doses, said Perl.

Investigators in the global phase III compared gilteritinib and salvage chemotherapy in adults with FLT3-mutated AML. Eligible patients had disease that proved refractory to induction chemotherapy or that was in untreated first relapse. The trial involved 371 patients, 247 randomized to gilteritinib and 124 to chemotherapy (low or high-intensity, selected prior to randomization). Crossover at disease progression was not allowed.

The trial had coprimary endpoints: OS and the composite of complete remission and complete remission with partial hematologic recovery (CR/CRh). Gilteritinib received FDA approval on the basis of an interim analysis, and Perl reported survival data for the first time.

The study population had a median age of 62. Perl said 88.4% of the patients had FLT3-ITD mutations, 8.4% had FLT3-TKD, 1.9% had both, and 1.3% had unconfirmed mutation status. Relapsed AML accounted for 60.6% of patients.

The results showed that patients randomized to gilteritinib had a 36% reduction in the survival hazard (95% CI 0.49-0.83, P=0.007). The gilteritinib group had a 12-month survival of 37% as compared with 17% for patients randomized to salvage chemotherapy. The CR/CRh rates were 34.0% and 15.3% for the gilteritinib and chemotherapy arms, respectively (P=0.0001), including CR rates in 21.1% and 10.5% (P=0.0106).

Treatment-emergent adverse events occurred more often in patients randomized to salvage chemotherapy, including febrile neutropenia (32% vs 21%), pyrexia (26% vs 15%), nausea (30% vs 13%), hypokalemia (27% vs 11%), diarrhea (28% vs 10%), leukopenia (17% vs 9%), and decreased appetite (17% vs 5%). The gilteritinib group had more cases of elevated liver enzymes (AST 24% vs 10%; ALT 24% vs 7%) and increased blood alkaline phosphatase (13% vs 2%). Anemia occurred in 33% of both groups.

Perl said studies of gilteritinib-containing regimens in front-line treatment of AML have already begun, noting that experience with midostaurin showed higher cure rates with FLT3 inhibition in untreated AML.

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