ASH: Quizartinib Monotherapy Active in Elderly with FLT3-ITD(+) Relapsed/Refractory AML

Final data from a Phase 2 study reported by Astellas and Ambit Biosciences during the 54th American Society of Hematology Annual Meeting and Exposition confirm the high degree of activity of quizartinib (AC220) monotherapy in patients ≥60 years of age with relapsed/refractory acute myeloid leukemia (AML) positive for FMS-like tyrosine kinase 3 internal tandem duplications, or FLT3-ITD(+).

Some activity is also observed in those who are FLT3-ITD negative, said Jorge E. Cortes, MD, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

“These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in elderly patients with relapsed/refractory FLT3-ITD positive AML,” Dr. Cortes said. “Of clinical significance in this elderly population, a number of patients refractory to prior therapy responded to quizartinib, with some patients able to bridge to potentially curative hematopoietic stem cell transplantation (HSCT) .”

FLT3-ITD in AML is associated with early relapse after standard chemotherapy and poor survival.

Quizartinib, an oral FLT3 receptor tyrosine kinase inhibitor (TKI) active against both ITD mutant and wild type FLT3, had shown promising activity in a Phase 1 study of patients with AML.

The Phase 2 study was conducted to assess efficacy and safety of quizartinib monotherapy in 271 patients who were FLT3-ITD(+) and FLT3-ITD(−). Cohort 1 included patients ≥60 years of age with AML relapsed <1 year or refractory to first-line chemotherapy; results from the 133 patients in this cohort comprised the basis for this analysis. Of these, 90 were FLT3 ITD(+) and  42 were FLT3-ITD(−). Among the FLT3-ITD(+) patients, 50% were male and median age was 70 years (range, 54–85 years); of the FLT3-ITD(−) patients, 46% were male and median age was 69 years (range, 60–78 years).

In an exploratory cohort in an additional 62 patients, the initial starting dose was quizartinib 200mg/day; this was reduced to 90mg/day (females) or 135 mg/day (males) for the confirmatory cohort due to Grade 3 QT prolongation. Treatment was  continuous during 28 day cycles.

Composite complete remission (CRc) rate was defined as complete remission (CR) plus complete remission with incomplete platelet recovery (CRp) plus complete remission with incomplete hematologic recovery (CRi).

For FLT3-ITD(+) patients, CRc rate was 53% (0 CR, 3% CRp, and 50% Cri); CRc plus PR was 74%. For FLT3-ITD(−) patients, CRc rate was 36% (2% CR, 2% CRp, and 31% CRi); CRc plus PR was 46%. Median duration of response was 10.4 weeks for FLT3-ITD(+) patients and 9.3 weeks for FLT3-ITD(−).

Of the patients refractory to last AML therapy, 70% of the FLT3-ITD(+) and 55% of the FLT3-ITD(−) patients achieved at least a PR with quizartinib.

Median survival was 25.3 weeks in FLT3-ITD(+) patients; 12 of 90 survived more than 12 months and 2 for more than 18 months. Median duration of quizartinib was 52.2 weeks. Among FLT3-ITD(−) patients, median survival was 19 weeks and 5 of 42 patients survived more than 12 months; median duration of quizartinib was 31.9 weeks.  Median survival was 32.2 weeks among those who had received an HSCT and 24.9 weeks among those who had not. At the last follow-up, 17 patients (13%) survived more than 1 year and 10 (8%) are alive.

Safety findings were primarily gastrointestinal toxicities, reversible QT prolongation, and myelosuppression that was possibly related to KIT inhibition, Dr. Cortes said. A randomized two-dose study—30mg vs. 60mg—in relapsed/refractory ITD(+) AML is currently accruing patients and a Phase 3 randomized study is planned at the end of 2013.