Gilteritinib is a potent, highly-selective oral fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor, which has been shown to elicit antileukemic responses in patients with relapsed/refractory (R/R) FLT3 mutation-positive (FLT3mut+) acute myeloid leukemia (AML).1 In November 2018, the US Food and Drug Administration (FDA) approved gilteritinib for the treatment of patients with FLT3mut+ R/R AML.
At the 60th Annual Society of Hematology Annual Meeting & Exposition, Keith Pratz, MD, from the Johns Hopkins University, Baltimore, US, presented updated results from the phase I dose-escalation/expansion study (NCT02236013) of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML. The aims of the study were to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of gilteritinib, and evaluate the safety and tolerability of gilteritinib in combination with chemotherapy.2
As of 8 October 2018, 66 AML patients were evaluable in the safety analysis set, of which the median age was 59.5 years (range, 23–77). FLT3 mutation status was available for all 66 patients; 54.5% (36/66) were FLT3mut+, 43.9% (29/66) were FLT3 wild-type and 1.5% (1/66) had unknown status.
Dose-escalation followed a 3+3 design, and successive cohorts of 3–6 patients received 40, 80, 120, or 200 mg/day gilteritinib. In the dose escalation and dose-expansion cohorts, patients were administered ≤ 2 cycles of a 7+3 chemotherapy induction regimen (cytarabine 100 mg/m2/day, days 1–7, and idarubicin 12 mg/m2/day, days 1–3), in combination with once-daily gilteritinib on days 4–17 (schedule 1). Following completion of schedule 1 dose-expansion cohort, a new cohort of patients were enrolled (n = 6) and gilteritinib administration was changed to days 8–21 (schedule 2) in combination with daunorubicin 90 mg/m2/day, administered on days 1–3. During consolidation, all patients received cytarabine (1.5 g/m2 every 12 hours on days 1, 3, and 5) and once-daily gilteritinib, on days 1–14, at the induction dose, for ≤ 3 cycles. Patients in the dose-expansion cohort of this study were administered gilteritinib at the recommended dose established during the dose escalation stage of this study.
Key findings in patients (n = 66) evaluable for response:
- DLTs were not observed during remission induction in the 40, 80, or 120 mg/day cohorts in gilteritinib induction schedule 2
- In the 200 mg/day cohort induction schedule, DLTs of prolonged neutropenia (n = 1) and neutropenic enterocolitis (n = 1) were observed
- The expansion dose and MTD were established at 120 mg/day
- Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 63.6% (42/66) of patients including febrile neutropenia 31.8% (21/66), thrombocytopenia 16.7% (11/66), neutropenia 16.7% (11/66) and decreased neutrophil count 16.7% (11/66)
- Treatment-related TEAEs which led to discontinuation include neutropenia and thrombocytopenia (n = 1), elevated alanine aminotransferase/aspartate aminotransferase (n = 1), decreased ejection fraction (n = 1) and congestive heart failure
- Efficacy in FLT3mut+ patients (n = 33)
- Median duration of response: 14.1 months
- Median overall survival: not reached
- Composite complete remission (CRc) rate, includes patients achieving complete remission (CR), complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery: 93.9% (31/33)
In an interview with the AML Global Portal, Keith Pratz reported a response rate of “over 90% in the FLT3 mutant AML population”, where “the combination seems to be very well tolerated and the forward dose in the combination of gilteritinib is the same dose that will be given in the relapsed/refractory setting.” In addition to this, Keith Pratz spoke about the future of the gilteritinib and chemotherapy combination in the front-line setting for the treatment of AML patients, where he noted that there “will be two large phase III studies” comparing the outcomes to the current standard of care treatment.