KEY TAKEAWAYS
- Phase 3 multicenter and open-label trial evaluated the efficacy and safety of GIL + AZA combination therapy in untreated adults with FLT3mut+ AML ineligible for aggressive chemotherapy.
- The primary aim of the trial was to measure the OS endpoint.
- The GIL + AZA group had a median OS of 9.82 months, while the AZA alone group had a median OS of 8.87 months.
- As determined by CRc, the event-free survival duration was 4.53 months for the combination of GIL and AZA and 0.03 months for AZA alone.
- The complete remission rates with consolidation were 58.1% for the combination of GIL and AZA and 26.5% for AZA alone.
The outcomes of therapy for individuals who have recently been diagnosed with FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) and are not qualified for aggressive chemotherapy are unsatisfactory. In this phase-3 trial, which was multicenter and open-label, untreated adults diagnosed with FLT3mut+ AML and deemed ineligible for intensive induction chemotherapy, were randomized in a 2:1 ratio. The participants were assigned to receive either gilteritinib (administered orally at a dose of 120 mg/d) and azacitidine (GIL + AZA) or azacitidine alone (AZA). The principal outcome measure was the overall survival (OS) endpoint. As of the interim analysis conducted on August 26, 2020, the treatment group consisted of 123 randomized patients, with 74 receiving GIL + AZA and 49 receiving AZA alone. There were 20.3% of patients who received GIL plus AZA, and 44.9% of patients who received AZA, and underwent subsequent therapy for AML, which included FLT3 inhibitors.
The median overall survival (OS) for patients treated with GIL and AZA was 9.82 months, while those treated with AZA alone had a median OS of 8.87 months. The hazard ratio was 0.916 with a 95% confidence interval of 0.529-1.585 and a P= .753. The clinical investigation was terminated in accordance with the predetermined threshold for futility as outlined in the study protocol. The median event-free survival rate was 0.03 months in both treatment groups. The duration of event-free survival, as determined by composite complete remission (CRc), was 4.53 months for the combination of GIL and AZA and 0.03 months for AZA alone. The hazard ratio was 0.686 with a 95% confidence interval of 0.433-1.087, and the P= 0.156. The complete remission rates with consolidation were 58.1% for the combination of GIL and AZA and 26.5% for AZA alone.
The difference between the two rates was 31.4%, with a 95% confidence interval of 13.1-49.7 and a P< 0.001. The rates of adverse events (AEs) were comparable between the combination of GIL and AZA (100%) and AZA alone (95.7%). However, the occurrence of AEs with a severity grade of ≥3 was 95.9% and 89.4%, respectively. Frequently observed adverse events associated with the combination of GIL and AZA comprise pyrexia, reported in 47.9% of cases, and diarrhea, reported in 38.4%. No significant difference was observed in the steady-state trough concentrations of gilteritinib between the treatment groups of GIL + AZA and gilteritinib. The combination therapy of GIL and AZA yielded notably elevated CRc rates while exhibiting comparable OS in contrast to AZA alone. The findings indicate that administering GIL and AZA as initial treatment is well-tolerated and safe for elderly or medically compromised individuals with FLT3mut+ AML. Additionally, there is evidence of positive clinical outcomes associated with this therapeutic approach.
Source: https://pubmed.ncbi.nlm.nih.gov/35917453/
Clinical Trail: https://clinicaltrials.gov/ct2/show/NCT02752035
Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, Chou WC, Laribi K, Esteve J, Altman JK, Havelange V, Watson AM, Gambacorti-Passerini C, Patkowska E, Liu S, Wu R, Philipose N, Hill JE, Gill SC, Rich ES, Tiu RV. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022 Oct 27;140(17):1845-1857. doi: 10.1182/blood.2021014586. PMID: 35917453.
