Gilteritinib/Chemotherapy Combination Safe and Effective in Newly Diagnosed AML

The addition of the type 1 FLT3 inhibitor gilteritinib (Xospata) to induction and consolidation chemotherapy, followed by maintenance gilteritinib monotherapy, was safe and tolerable with promising initial efficacy in patients with newly diagnosed acute myeloid leukemia (AML), according to findings from a phase 1b trial (NCT02236013) published in the Journal of Clinical Oncology.¹

Results from the study showed that patients with FLT3-mutated disease (n = 36) achieved a composite complete response (CRc) rate of 89%, including an 83% complete response (CR) rate at day 56. Patients with FLT3 wild-type disease (n = 22) experienced a CRc rate of 50%, including a 56-day CR rate of 41%. The median overall survival (OS) was 46.1 months and 38.7 months in the FLT3-mutant and FLT3 wild-type subgroups, respectively. No significant differences were observed between patients who were induced withidarubicin vs daunorubicin (P = .2) or those who started gilteritinib treatment on day 4 vs day 8 (P = .2).¹

The study was comprised of 4 parts including dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib dosing schedules, and, in part 4, gilteritinib was evaluated after being administered continuously during consolidation.

During the dose-escalation portion of the trial, which enrolled 21 patients, 1 patient treated with gilteritinib at a daily dose of 40 mg experienced 2 dose-limiting toxicities (DLTs), both were attributed to excess exposure to anthracycline. Additional DLTs occurred in 2 patients treated at the 200 mg dose level: fatal neutropenic colitis and delayed count recovery.

In the dose expansion phase, 58 patients were treated at the maximum tolerated dose (MTD) of 120 mg daily. Eighty-three percent of patients took all of the planned doses of gilteritinib, and the remaining 10 patients took 82% of planned doses on average. The 60-day mortality rate was 1.3% with 3 patients dying from fungal sepsis (n = 1) and infections (n = 2) during the induction phase.¹

In November 2018, gilteritinib was approved by the FDA for the treatment of adult patients with relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test.² The indication was supported by findings from the interim analysis of the phase 3 ADMIRAL trial (NCT02421939), which showed that at a median follow-up of 4.6 months (range, 2.8-15.8), adult patients with relapsed/refractory AML with a FLT3 ITD, D835, or I836 mutation who received gilteritinib monotherapy (n = 138) achieved a complete remission or complete remission with partial hematologic recovery rate of 21% (95% CI, 14.5%-28.8%). Additionally, patients who were red blood cell (RBC) and/or platelet transfusion dependent (n = 106) achieved independence from RBC and platelet transfusions during any 56-day post-baseline period at a rate of 31.1%.

In the phase 1 trial published in the Journal of Clinical Oncology, the primary objectives of the dose-escalation and a dose-expansion phases were to identify DLTs; determine the MTD of gilteritinib in combination with cytarabine/idarubicin or daunorubicin remission induction given in a 7+3 regimen; and evaluate the safety and tolerability of gilteritinib administered with intensive induction and consolidation therapy, as maintenance after intensive therapy, and given with a 7+3 regimen using an alternative anthracycline and gilteritinib schedule. The pharmacokinetics gilteritinib plus intensive therapy was a secondary objective, with efficacy, the impact of FLT3 mutations, and pharmacodynamics representing exploratory objectives.¹

Eligible patients needed to be 18 years of age or older with newly diagnosed, treatment-naïve de novo AML documented within 28 days of enrollment. In the dose-escalation phase (part 1), patients were treated with gilteritinib at doses of 40 mg, 80 mg, 120 mg, or 200 mg once daily on day 4 continuing for 14 days, plus intravenous idarubicin 12 mg/m² once per day on days 1 through 3 and cytarabine 100 mg/m² once per day on days 1 through 7. The dose-expansion portion (part 2) treated patients with the MTD of gilteritinib (120 mg).

Part 3 evaluated 2 cohorts of patients—alternative induction regimens were evaluated with gilteritinib examined starting day 8 vs day 4 and daunorubicin was compared with idarubicin. Part 4 evaluated the effect of continuous gilteritinib exposure during consolidation.

Patients entered maintenance following induction and consolidation in all parts of the trial. Maintenance consisted of daily gilteritinib at the assigned dose level for 28-day cycles up to a total of 26 cycles. Interruption for allogeneic transplant was allowed.

Response-evaluable patients treated at the MTD (n = 58) had a median age of 59 years (range, 24-77). Most patients had an intermediate level of cytogenetic risk (86%) and were males (64%). Half of the patients in the efficacy population received allogeneic hematopoietic stem cell transplantation on the study or during follow-up. FLT3 status included wild-type (38%), ITD mutated (43%), D835 mutated (9%), both ITD and D835 mutated (10%), and NPM1 mutated (33%).¹

Most patients treated at the MTD received a single course of induction (95%). Among patients who were treated with 2 courses of induction (n = 3), 2 died due to infection and 1 did not experienced a response and withdrew.

In terms of recovery of peripheral blood counts, 15 patients who achieved a CR did not recover neutrophils and platelets until after day 42 of induction, with a median time to recovery of 13 days (range, 5-20) after last marrow assessment. The CR rates at day 42 were 27% for patients who were FLT3 wild-type and 53% among those with FLT3-mutated disease.

The median time to count recovery was 41 days (interquartile range, 35-48) for patients who were treated withgilteritinib at the MTD who achieved a CR as best response after induction (n = 39). Most of these patients (n = 27) went ahead with consolidation and the median time to count recovery of 36 days.

In the safety population (n = 78), most patients experienced a grade 3/4 treatment-emergent adverse effect (TEAE; 93.6%). The most common grade 3/4 TEAEs included febrile neutropenia (66.7%), thrombocytopenia (20.5%), neutropenia (17.9%), and anemia (15.4%).

References

1. Pratz KW, Cherry M, Altman JK, et al. Gilteritinib in combination with induction and consolidation chemotherapy and as maintenance therapy: a phase IB study in patients with newly diagnosed AML. J Clin Oncol. Published online June 28, 2023. doi:10.1200/JCO.22.02721
2. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutatation. News release. FDA. November 28, 2018. Accessed July 19, 2023. https://www.fda.gov/drugs/fda-approves-gilteritinib-relapsed-or-refractory-acute-myeloid-leukemia-aml-flt3-mutatation