Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia

Abstract

The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3^mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3^mut+ AML.

Fig. 1. Treatment disposition, CONSORT diagram.

Reasons for exclusion prior to randomization were negative FLT3 mutation status, unclear relapsed/refractory status, other inclusion criteria not met, patient withdrawal, other exclusion criteria met, investigator decision, medical records for hospitalization not available, death, and economic reasons. *Indicates patients on high-dose chemotherapy who completed one cycle of treatment with a composite complete remission and were taken off of treatment or completed two cycles of treatment. FLAG fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor, FLT3 FMS-like tyrosine kinase 3, MEC mitoxantrone, etoposide, and intermediate-dose cytarabine.

Fig. 2. Overall survival by treatment group (intention-to-treat population) and subgroup analysis of overall survival.

A Kaplan–Meier curve of overall survival (primary endpoint). The intention-to-treat population includes all randomized patients. The predetermined two-sided significance level was 0.00454 based on the number of observed overall survival events. B Subgroup analyses of overall survival. Preselected high-intensity therapy included FLAG or MEC; preselected low-intensity chemotherapy consisted of LoDAC. CI confidence interval, CRc composite complete remission, ECOG Eastern Cooperative Oncology Group, FLAG fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor, FLT3 FMS-like tyrosine kinase 3, HR hazard ratio, HSCT hematopoietic stem cell transplantation, IRT interactive response technology, ITD internal tandem duplication, LoDAC low-dose cytarabine, MEC mitoxantrone, etoposide, and intermediate-dose cytarabine, NE not estimable, SC salvage chemotherapy, TKD tyrosine kinase domain.

Fig. 3. Event-free survival by treatment group (intention-to-treat population).

Kaplan–Meier curve of event-free survival (a key secondary endpoint). The predetermined two-sided significance level was 0.04011. CI confidence interval, HR hazard ratio.