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Quizartinib prolongs overall survival in patients with FLT3-internal tandem duplication–mutated relapsed/refractory AML in the phase III QuANTUM-R trial

The QuANTUM-R trial evaluates the efficacy and safety of quizartinib versus salvage chemotherapy in patients with relapsed/refractory FLT3-ITD–mutated AML. The first results presented by Cortes et al. showed a higher median overall survival with quizartinib compared to salvage chemotherapy (27 weeks verus 20.4 weeks). The incidence of treatment-emergent adverse events was comparable between the 2 arms.

FLT3-internal tandem duplication (FLT3-ITD) is a common driver mutation in acute myeloid leukemia (AML) associated with high leukemic burden and poor prognosis—high risk of relapse, decreased response to salvage therapy, and shorter overall survival (OS). Currently, there are no approved targeted therapies for patients with relapsed/refractory (R/R) FLT3-ITD–mutated AML, which represents a high unmet medical need. Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor (FLT3i) shown in phase 2 trials to have promising single-agent antileukemic activity and a manageable safety profile.

In the global, phase 3, randomized, controlled trial QuANTUM-R, efficacy and safety of quizartinib was evaluated versus salvage chemotherapy (SC) in patients with R/R FLT3-ITD–mutated AML. Primary endpoint was OS.

Patients ≥18 years with FLT3-ITD–mutated AML who were refractory to or relapsed ≤6 months after first complete remission after standard AML therapy, with or without hematopoietic stem cell transplantation (HSCT) were randomized 2:1 to receive quizartinib (60-mg, with a 30-mg lead-in) or investigator’s choice SC, which was selected prior to randomization. Allowed SC regimens were low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (GCSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or HSCT. Prior therapy with FLT3i (except the multikinase inhibitor, midostaurin) was not allowed. Patients receiving HSCT in the quizartinib arm were allowed to resume quizartinib therapy following transplant.

Patients were randomized to quizartinib (n=245) and SC (n=122 [LoDAC, n=29; MEC, n=40; FLAG-IDA, n=53]). Median follow-up was 102.4 weeks at study analysis cutoff. Treatment groups were well-balanced for baseline characteristics. OS hazard ratio of quizartinib relative to SC was 0.76 (95% CI 0.58-0.98; stratified log-rank test, 1-sided P=0.0177). Median OS was 27 weeks (95% CI 23.1-31.3) and 20.4 weeks (95% CI 17.3-23.7) for patients treated with quizartinib and SC, respectively. Estimated survival probability at 52 weeks was 27% for the quizartinib arm and 20% for the SC arm. Rates of treatment-emergent adverse events were comparable between the 2 arms. Only 2 patients discontinued quizartinib due to QTcF prolongation. No events of torsades de pointes were reported. The quizartinib safety profile appears consistent with that observed before at similar doses.

In conclusion, the first results of the QuANTUM-R trial, showed that single-agent quizartinib significantly prolonged OS in patients with R/R FLT3-ITD–mutated AML compared with SC. These pivotal data confirm the efficacy and safety of quizartinib and the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3i. These results represent the first positive phase 3 trial to demonstrate improved OS with FLT3i in the R/R FLT3-ITD–mutated AML setting.



Cortes JE, Khaled S, Martinelli G, et al. Quizartinib significantly prolongs overall survival in patients with flt3-internal tandem duplication–mutated (mut) relapsed/refractory aml in the phase 3, randomized, controlled quantum-r trial. Presented at EHA 2018; abstract LB2600.

Spreker Jorge Cortes


Prof. Jorge Cortes, MD, The University of Texas, MD Anderson Cancer Center, Houston, United States


Zie: Keyslides


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