This study is the first to show significantly improved OS from single-agent treatment in this particularly difficult to treat population.
Further evidence for combating FLT3-internal tandem duplication (FLT3-ITD) mutated relapsed/refractory acute myeloid leukemia (AML) has been reported at the 23rd Congress of the European Hematology Association. Jorge E. Cortes, MD, and colleagues found patients with relapsed/refractory AML with FLT3-ITD mutations who received single-agent quizartinib had a 24% reduction in the risk of death compared with those who received salvage chemotherapy (hazard ratio [HR], 0.76).
Quizartinib is a small-molecule receptor tyrosine kinase inhibitor that targets the proto-oncogene FLT3 (also known as CD135). It is taken orally once daily, and is a highly potent and selective FLT3 inhibitor.
Results from the global, phase III, randomized, controlled trial (ClinicalTrials.gov identifier: NCT02039726) showed the median overall survival (OS) was 6.2 months for patients treated with quizartinib, compared with 4.7 months for patients treated with salvage chemotherapy. The estimated survival probability at 1 year was 27% for patients who received quizartinib and 20% for patients treated with salvage chemotherapy.
“I have been using quizartinib since the initial phase I study, so I am very familiar with its efficacy and safety. In that regard, what we found is not surprising. But I was, overall, surprised because it has been so difficult to achieve any such survival benefit with so many approaches that have been investigated in salvage AML. Nothing has really helped until now,” said Cortes, who is the Deputy Chair of the Department of Leukemia in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston, Texas.
He said these findings represent the first reported clinical data demonstrating that a single agent can significantly improve OS in this particularly difficult to treat population. Previous phase II trials showed quizartinib had antileukemic activity and a manageable safety profile.
In the current phase III trial, the median follow-up was 102.4 weeks at the study analysis cutoff. Median treatment duration with quizartinib was 4 cycles of 28 days vs 1 cycle (range, 1–2) in the salvage chemotherapy arm. The median relative dose intensity for quizartinib was 89%.
The incidences of treatment-emergent adverse events (AEs) were comparable between patients who received quizartinib (n = 241) and those who received salvage chemotherapy (n = 94). The most common AEs (any grade, and occurring in more than 30% of patients) included nausea (48% in the quizartinib arm vs 42% with chemotherapy), thrombocytopenia (39% vs 34%, respectively), fatigue (39% vs 29%), musculoskeletal pain (38% vs 29%), pyrexia (38% vs 45%), anemia (37% vs 32%,), neutropenia (34% vs 26%), febrile neutropenia (34% vs 28%), vomiting (33% vs 21%), and hypokalemia (32% vs 28%).
Cortes said because of this agent’s high selectivity, the safety profile is very favorable. “The main adverse event we had seen throughout the development of quizartinib was QTc prolongation. However, we have found a dose that has a good balance between efficacy and safety; so in this study the rate of QTc prolongation was low, and in no instance did it result in serious arrhythmias. Other than that, the adverse events observed were mostly low grade and manageable,” he told Cancer Network.