SUMMARY: The FDA on July 20, 2023 approved Quizartinib (VANFLYTA®) with standard Cytarabine and Anthracycline induction and Cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed Acute Myeloid Leukemia (AML) that is FLT3 Internal Tandem Duplication (ITD)-positive, as detected by an FDA-approved test. FDA also approved LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic for Quizartinib.
The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy, or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.
The Fms-Like Tyrosine kinase 3 (FLT3) protein is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the hematopoietic stem cell surface (transmembrane). FLT3 normally promote cell survival, growth, and differentiation. FLT3 plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML. Approximately 25% of patients with newly diagnosed AML have FLT3-ITD mutations and approximately 7% have point mutations in the Tyrosine Kinase Domain (TKD). FLT3-ITD (Internal Tandem Duplication) mutation is caused by tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations have poor outcomes with shorter remission duration and significantly decreased Leukemia Free and Overall Survival.
Quizartinib is an oral, highly potent, selective, Type 2 FLT3 inhibitor. This agent in combination with chemotherapy showed antitumor activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML.
QuANTUM-First is a randomized, double-blind, placebo controlled, global, Phase III trial in which the efficacy of Quizartinib with chemotherapy was evaluated in patients with newly diagnosed FLT3-ITD positive AML aged 18–75 years. In this study, 539 patients (N=539) with newly diagnosed FLT3-ITD positive AML were randomly assigned 1:1 to receive chemotherapy plus Quizartinib (N=268) or placebo (N=271). Treatment consisted of induction with standard 7 plus 3 induction regimen of Cytarabine 100 mg/m2 daily (or 200 mg/m2 daily per institutional standard) by continuous IV from Days 1-7 and anthracycline (Daunorubicin 60 mg/m2 daily or Idarubicin 12 mg/m2 daily, by IV infusion on Days 1, 2, and 3, then Quizartinib 40 mg orally or placebo once daily, starting on day 8, for 14 days. Patients in complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose Cytarabine plus Quizartinib (40 mg orally daily) or placebo, allo- Hematopoietic Stem Cell Transplantation (HSCT), or both as consolidation therapy, followed by continuation of single-agent Quizartinib or placebo for up to 3 years. There was no re-randomization at the initiation of post-consolidation therapy. Patients who proceeded to HSCT initiated maintenance therapy after HSCT recovery. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay. This study included patients aged 18 to 75 years, 55% male and 45% female, with newly diagnosed primary or secondary AML harboring a FLT3-ITD activating mutation, with an allelic ratio of 3% or more. The median age was 56 years. The aim of this study was to assess the effect of Quizartinib versus placebo on Overall Survival in patients with FLT3-ITD-positive newly diagnosed AML. The Primary end point of the trial was Overall Survival (OS). Secondary end points included Event-Free Survival (EFS), post induction rates of Complete Remission (CR) rate, composite CR (CRc) rate, Safety, and pharmacokinetics.
At a median follow up of 39.2 months, the median Overall Survival was 31.9 months for Quizartinib versus 15.1 months for placebo (HR=0.78; P=0.032), a 22% reduction in the risk of death. The CR rate in the Quizartinib group was 55%, with median response duration of 38.6 months, whereas the CR rate in those receiving placebo was 55% with median response duration of 12.4 months. Approximately 42% of patients treated with Quizartinib versus 38% treated with placebo were MRD negative at the time of Complete Remission or Complete Remission with incomplete neutrophil or platelet recovery. However, patients in both groups who were MRD negative had improved Overall Survival (HR 0.57), compared with those who remained MRD positive. The most common Grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups, and neutropenia in the Quizartinib group.
It was concluded that the addition of Quizartinib to standard chemotherapy with or without allo-HSCT, followed by continuation monotherapy for up to 3 years, resulted in improved Overall Survival in adults patients with FLT3-ITD-positive newly diagnosed AML, and provides a new, effective, and generally well tolerated treatment option for this patient group. The authors added that this is the first time a FLT3 inhibitor was studied in patients aged 18-75 years and is specifically approved for patients who have the worst FLT3 mutation, the ITD mutation.
Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Erba HP, Montesinos P, Kim H-J, et al. on behalf of the QuANTUM-First Study Group. The Lancet 2023;401:1571-1583.
