Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial

Summary

Background

Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia.

Methods

We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed.

Findings

Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2.

Interpretation

Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses.

Funding

Ambit Biosciences/Daiichi Sankyo.

Introduction

Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene are common in acute myeloid leukaemia.¹ The most frequent mutation is an internal tandem duplication (ITD), occurring in approximately 25% of patients with acute myeloid leukaemia² and characterised by high white blood cell and bone marrow blast counts as well as a high risk of relapse after standard chemotherapy.3, 4, 5, 6 Patients with FLT3-ITD mutations (ie, FLT3-ITD-positive patients) are also less likely to respond to salvage chemotherapy and have shorter survival following relapse than FLT3-ITD-negative patients.3, 7 Additionally, older patients similarly have poor responses, high risk of relapse, and shorter overall survival than younger patients, warranting the need for improved treatment options, especially for FLT3-ITD-positive patients or those unable to tolerate standard chemotherapy (eg, the elderly).8, 9, 10

Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor being investigated for the treatment of FLT3-ITD-positive acute myeloid leukaemia.¹¹ In a phase 1 trial,¹² quizartinib showed complete target inhibition in biomarker assays and clinical activity in FLT3-ITD-positive and FLT3-ITD-negative patients with relapsed or refractory acute myeloid leukaemia. Quizartinib was generally well tolerated with a manageable safety profile. The maximum tolerated dose was 200 mg per day, and the dose-limiting toxicity was grade 3 QT interval corrected using Fridericia's formula (QTcF) prolongation.¹² Therefore in this phase 2 study, we aimed to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD-positive and FLT3-ITD-negative patients with refractory or relapsed acute myeloid leukaemia.

Research in context

Evidence before this study

We searched PubMed for published studies of FMS-like tyrosine-kinase 3 (FLT3) inhibitors for the treatment of relapsed or refractory acute myeloid leukaemia. We used the search terms “FLT3 inhibitor” OR “FLT3-ITD inhibitor” AND “relapsed or refractory AML” AND “clinical trial”. We did not restrict the searches by date or language. The current evidence shows that patients with relapsed or refractory acute myeloid leukaemia have a poor prognosis marked by limited response to standard salvage chemotherapy and short survival following relapse, especially in those with FLT3 internal tandem duplication (ITD)-positive disease or individuals of old age, or both. Treatment options for patients with acute myeloid leukaemia are limited to standard chemotherapy, which is largely ineffective. At the time of this submission, no FLT3 inhibitors were approved for the treatment of relapsed or refractory, FLT3-mutated acute myeloid leukaemia. However, the recent US Food and Drug Administration and European Commission approval of midostaurin, a multikinase inhibitor, in combination with standard chemotherapy provides a new treatment option for patients with newly diagnosed FLT3-mutated acute myeloid leukaemia, yet does not fulfil the unmet need in relapsed or refractory, FLT3-mutated acute myeloid leukaemia. Furthermore, elderly patients with this disease, particularly those who are unable to tolerate chemotherapy, still need more effective and tolerable therapeutic options.

Added value of this study

Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor. This phase 2 trial included elderly patients who relapsed within 1 year after first-line chemotherapy or were primary refractory to first-line treatment (ie, cohort 1) and those 18 years or older who were refractory to or relapsed after salvage chemotherapy or after haemopoietic stem cell transplantation (ie, cohort 2). This study showed that quizartinib is highly active and well tolerated as a single agent in patients with FLT3-ITD-positive, relapsed or refractory acute myeloid leukaemia and is active in some patients with FLT3-wild type acute myeloid leukaemia.

Implications of all the available evidence

FLT3-ITD is a driver mutation that presents with high leukaemic burden and is associated with poor prognosis. In these patient populations, treatment with quizartinib resulted in a high proportion of responders, including in elderly patients (cohort 1), and allowed approximately a third of patients to bridge to haemopoietic stem cell transplantation (cohort 2). These findings warrant further evaluation of quizartinib as an oral, highly potent, and selective next-generation FLT3 inhibitor, including in this setting and in combination with induction chemotherapy.