Quizartinib prolongs survival of newly diagnosed FLT3-ITD-mutated AML

Quizartinib improves overall survival when combined with standard induction and consolidation therapy, and as continuation therapy as a single agent for up to 3 years in patients with newly diagnosed acute myeloid leukaemia (AML) characterised by internal tandem repeats within the FLT3 gene (FLT3-ITD-mutated), results from the phase 3 QuANTUM-First study demonstrated.

FLT3-ITD is among the most common driver mutations in AML (approximately 25% of all AML cases), and is associated with poor prognosis, high relapse rates, and inferior overall survival. The prognosis of FLT3-TKD mutations remains unclear [1,2]. The RATIFY study (NCT00651261) showed an improved overall survival in FLT3-mutated AML patients with midostaurin, albeit with a high rate of relapse [3]. Quizartinib is a highly potent and selective second-generation type II FLT3 inhibitor that demonstrated a signal of clinical efficacy and a manageable safety profile in a phase 2 trial [4]. The QuANTUM-First trial (NCT02668653) aimed to determine if the addition of quizartinib to standard induction and post-remission consolidation therapy, followed by quizartinib continuation therapy for up to 3 years, improves survival compared with chemotherapy alone. Dr Harry Erba (Duke Cancer Institute, NC, USA) presented the results.

The study enrolled 533 patients (18–75 years old) who were randomised 1:1 to induction therapy (cytarabine/daunorubicin) plus quizartinib or induction therapy plus placebo. In the quizartinib arm, 173 patients entered the consolidation phase (HiDAC/quizartinib and/or allogeneic HCT) and 116 patients thereafter continued with single-agent quizartinib. In the placebo arm, 175 patients entered the consolidation phase (HiDAC/placebo and/or allogeneic HCT); subsequently, 92 patients continued with placebo consolidation.

The median overall survival (primary endpoint) was 31.9 months in the quizartinib arm versus 15.1 months in the placebo arm (HR 0.776; P=0.0324). A total of 193 patients (n=102 in the quizartinib arm, n=91 in the placebo arm) received allogeneic HCT. Overall survival censored for allogeneic HCT also numerically favoured quizartinib, but did not reach significance at this time point (HR 0.752; P=0.055). Complete remission was comparable between arms, however, the duration of complete remission was 38.6 months in the quizartinib arm versus 12.4 months in the placebo arm.

The safety of quizartinib combined with intensive chemotherapy and as continuation monotherapy was generally manageable, with no new safety signals. Discontinuation due to treatment-emergent adverse events was observed in 20.4% of patients in the quizartinib arm versus 8.6% in the placebo arm.

“These data have the potential to change the standard-of-care for the treatment of adult patients with newly diagnosed FLT3-ITD-mutated AML,” Dr Erba concluded.

1. Levis M. Hematology Am Soc Hematol Educ Program. 2013;2013:220–226.
2. Kottaridis PD, et al. Blood. 2001;98:1752–1759.
3. Stone RM, et al. N Engl J Med. 2017;377:454–464.
4. Takahashi T, et al. Int J Hematol. 2019;110:665–674.
5. Erba H, et al. Quizartinib prolonged survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. Abstract S100. EHA2022 Hybrid Congress, 09–12 June.

 

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Posted on 1 July 2022