Summary Basis of Decision for Vanflyta

Clinical Pharmacology

Vanflyta contains quizartinib, a small molecule inhibitor of the feline McDonough sarcoma (FMS)-related receptor tyrosine kinase (FLT3). Both quizartinib and its major circulating active metabolite AC886 bind to the adenosine triphosphate (ATP) binding pocket of FLT3 with comparable affinity. Through this interaction, quizartinib and AC886 inhibit FLT3 kinase activity, preventing autophosphorylation of the receptor, inhibiting further downstream FLT3 receptor signaling, and blocking FLT3-internal tandem duplication (ITD)-dependent cell proliferation.

Clinical pharmacology data was provided through reports on human pharmacodynamic and pharmacokinetic studies.

Pharmacodynamic results showed that administration of either 20 or 30 mg/day of quizartinib resulted in plasma levels that achieved rapid and near complete FLT3 inhibitory activity.

Pharmacokinetic results showed that following oral administration to healthy subjects under fasted conditions, the median time to the maximum observed plasma concentration (C_max) of quizartinib and AC886 was approximately 4 hours and 5 to 6 hours, respectively. Quizartinib is primarily metabolized by cytochrome P450 3A (CYP3A) in vitro and is extensively metabolized in vivo via oxidative and reductive pathways. The main route of excretion for quizartinib-associated radioactivity was in the feces (76.3%).

Increases in quizartinib exposure are expected with concomitant use of strong CYP3A inhibitors (e.g., ketoconazole). Co-administration of quizartinib with a CYP3A inducer decreased quizartinib C_max and exposure.

No dosage adjustment is recommended in patients with mild to moderate hepatic or renal impairment. Vanflyta has not been studied in patients with severe hepatic or renal impairment.

Population pharmacokinetic analyses did not identify clinically relevant differences in quizartinib or AC886 exposure according to age, weight, sex, or race.

Overall, the review of clinical pharmacology studies did not identify issues that would preclude authorization of the product for the intended patient population. The data provided by these studies support the use of Vanflyta for the recommended indication.

For further details, please refer to the Product Monograph for Vanflyta, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Vanflyta was evaluated in the pivotal randomized, double-blind, placebo-controlled, Phase III QuANTUM-First study. The study enrolled 539 adult patients between 20 and 75 years of age who were newly diagnosed with FLT3-ITD positive acute myeloid leukemia (AML). Each patient’s FLT3-ITD status was determined prospectively using a clinical study assay. Patients were stratified by age (less than 60 years versus [vs.] 60 years and older), white blood cell count at diagnosis (less than 40 x 10⁹/L vs. 40 x 10⁹/L or higher), and region (North America; Europe; or Asia, Australia, and South America). Patients were randomized 1:1 to receive once-daily doses of Vanflyta 35.4 mg (total number [n] = 268) or placebo (n = 271) for two weeks in each 28-day cycle in combination with standard chemotherapy (induction followed by consolidation for responding patients), followed by maintenance monotherapy with Vanflyta (26.5 mg once daily for two weeks and 53 mg once daily thereafter) or placebo for up to 36 cycles (28 days/cycle).

For induction chemotherapy, patients received up to two cycles of either daunorubicin (60 mg/m²/day intravenous [IV] on days 1, 2 and 3) or idarubicin (12 mg/m²/day IV on days 1, 2 and 3) with cytarabine (100 mg/m²/day or 200 mg/m²/day allowed if institutional or local standard, IV infusion for 7 days), followed by post-remission therapy which consisted of up to four cycles of consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Consolidation chemotherapy consisted of cytarabine 3.0 g/m² for patients under 60 years of age and 1.5 g/m² for patients 60 years or older, administered every 12 hours by IV infusion on days 1, 3 and 5. Patients who proceeded to HSCT stopped receiving study treatment 7 days before the start of a conditioning regimen and initiated maintenance therapy after recovery from the HSCT.

The two randomized treatment groups were generally balanced with respect to baseline demographics, disease characteristics, and stratification factors. Of the randomized patients, the median age was 56 years (range: 20 to 75 years); 54% were female; 60% were White, 29% were Asian, 1% were Black, and 10% were from other races. Eighty-four percent had an Eastern Cooperative Oncology Group (ECOG) baseline performance status of 0 or 1. The majority of the patients (72%) had intermediate-risk cytogenetics at baseline. The FLT3-ITD variant allelic frequency (VAF) was 3 to 25% in 36% of patients, greater than 25 to 50% in 52% of patients, and greater than 50% in 12% of patients.

The primary efficacy endpoint was overall survival (OS), defined as the time from randomization until death from any cause. The median follow-up time was 39.2 months. The study demonstrated a statistically significant and clinically meaningful improvement in OS, with a 22.4% reduction in the risk of death in patients treated with Vanflyta compared to those treated with placebo (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.62, 0.98).

In an exploratory subgroup analysis of 119 patients who received maintenance therapy with Vanflyta or placebo following allo-HSCT, the OS HR was 1.62 (95% CI: 0.62, 4.22), indicating an inconsistent trend in OS benefit in the Vanflyta arm for this patient subgroup compared to the overall patient population.

Event-free survival (EFS) was the key secondary efficacy endpoint. The primary analysis of EFS, based on the definition of induction treatment failure as failure to achieve complete remission (CR) within 42 days of the start of the last cycle of induction chemotherapy, was not statistically significant (HR: 0.916; 95% CI: 0.754, 1.114).

The complete remission (CR) rate (the percentage of subjects achieving CR after induction) was 54.9% in the Vanflyta arm (95% CI: 48.7, 60.9) with a median duration of CR of 38.6 months (95% CI: 21.9, not estimable). The CR rate in the placebo arm of 55.4% (95% CI: 49.2, 61.4) with a median duration of CR of 12.4 months (95% CI: 8.8, 22.7).

Overall, Vanflyta in combination with standard induction and consolidation chemotherapy, followed by Vanflyta monotherapy maintenance treatment, demonstrated a statistically significant and clinically meaningful improvement in OS in adult patients with newly diagnosed FLT3-ITD-positive AML. The OS results from the QuANTUM-First study are considered substantial evidence of clinical effectiveness, supporting the recommended condition of use for Vanflyta. In addition, this study was initiated prior to the authorization of midostaurin for the treatment of newly diagnosed AML. As it enrolled adult patients up to 75 years of age with newly diagnosed, FLT3-ITD-positive AML, it provided supportive data in older adults as well as support for an alternative FLT3-ITD-targeted treatment.

Indication

The New Drug Submission for Vanflyta was filed by the sponsor with the following proposed indication:

Vanflyta (quizartinib) is indicated in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as maintenance monotherapy following consolidation, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) positive.

To support safe and effective use of the product, the indication was modified to reflect the design of the pivotal study QuANTUM-First, where Vanflyta maintenance monotherapy is part of the regimen, rather than a standalone indication. In addition, caveat statements were added to disclose the uncertainty regarding the benefit of Vanflyta maintenance monotherapy following allo-HSCT and to highlight the requirement for a validated test to confirm the FLT3-ITD status before initiating Vanflyta treatment. Accordingly, Health Canada approved the following indication:

Vanflyta (quizartinib) in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by Vanflyta maintenance monotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) positive.

Improvement in overall survival has not been demonstrated for maintenance monotherapy following allogeneic hematopoietic stem cell transplantation.

A validated test is required to confirm the FLT3-ITD status of AML.

For more information, refer to the Product Monograph for Vanflyta, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Vanflyta was evaluated in the pivotal QuANTUM-First study, described in the Clinical Efficacy section.

Throughout the pivotal study, the most common adverse reactions (occurring in 20% or more of patients) in the Vanflyta arm were: febrile neutropenia (44.2%), diarrhea (37.0%), nausea (34.0%), sepsis (30.2%), abdominal pain (29.4%), neutropenia (29.1%), headache (27.5%), and vomiting (24.5%). The most common Grade 3 or 4 adverse reactions (occurring in 5% or more of patients) were febrile neutropenia (43.4%), neutropenia (26.0%), sepsis (18.5%), thrombocytopenia (12.8%), fungal infections (5.7%), and anemia (5.7%). The most common serious adverse reactions (occurring in 2% or more of patients) in the Vanflyta arm were febrile neutropenia (10.9%), neutropenia (3.0%), fungal infections (2.3%) and herpes infections (2.3%).

Adverse reactions with a fatal outcome were sepsis (5.0%), fungal infections (0.8%), and cardiac arrest (0.4%). The most common adverse reactions (occurring in 2% or more of patients) associated with dose interruption of Vanflyta were neutropenia (10.6%), thrombocytopenia (4.5%), and prolonged QT interval on an electrocardiogram (2.6%). The most common adverse reactions (occurring in 2% or more of patients) associated with dose reduction of Vanflyta were neutropenia (9.1%), thrombocytopenia (4.5%), and prolonged QT interval on an electrocardiogram (3.8%). The most common adverse reactions (occurring in 1% or more of patients) associated with permanent discontinuation of Vanflyta were sepsis (5%) and thrombocytopenia (1.1%).

Of the 533 patients with newly diagnosed AML in the QuANTUM-First study 134 (25.1%) were 65 years of age and older, while 2 (0.4%) were 75 years of age. A higher incidence of fatal infections was reported in patients 65 years of age and older, compared to younger patients (13% vs. 5.7%), especially in the early treatment period. Discontinuations were reported in 29% of patients 65 years of age and older, and in 16.4% of younger patients. Clinical studies of Vanflyta did not include sufficient numbers of patients 75 years of age and older to determine whether they respond differently from younger adult patients.

Vanflyta prolonged the QT interval in a dose- and concentration-dependent manner. Torsades de pointes, cardiac arrest, and sudden death have been reported in patients receiving Vanflyta. A Serious Warnings and Precautions box describing the risk of QT interval prolongation and related cardiac complications as well as ways to monitor and mitigate these risks has been included in the Product Monograph for Vanflyta.

The safety of Vanflyta was further evaluated using safety data from the All AML Pool, a pooling group that included patients from multiple completed Vanflyta AML clinical studies. The safety findings were generally consistent with those in the pivotal study.

Overall, based on the data from the pivotal study, Vanflyta has an acceptable safety profile, under the authorized conditions of use. The identified safety issues can be managed through labelling and monitoring. A Risk Management Plan, including additional risk minimization measures for managing the risk of QT interval prolongation in the form of a Healthcare Professional (HCP) Guide and a Patient Card, was submitted, reviewed by Health Canada, and considered acceptable. Appropriate warnings and precautions are in place in the Product Monograph for Vanflyta to address the identified safety concerns. For more information, refer to the Product Monograph for Vanflyta, approved by Health Canada and available through the Drug Product Database.

Primary pharmacology study results showed that quizartinib bound to its target feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) with the highest affinity (dissociation constant [Kd] = 1.3 nM) over a panel of 441 kinases. Quizartinib bound with less affinity to tyrosine protein kinase (KIT; Kd = 4.9 nM) and showed affinity for a few other class III receptor tyrosine kinases (RTKs) including colony stimulating factory 1 receptor (CSF1R)/FMS (Kd = 9.6 nM), platelet-derived growth factor receptor beta (PDGFRβ; Kd = 14 nM), PDGFRα (Kd = 8.4 nM), and non-class III RTK, RET (Kd = 7.1 nM). The biochemical potency and selectivity of AC886, the major metabolite of quizartinib, appeared to be similar to the parent compound.

Based on in vitro studies conducted with a panel of 118 enzymes, receptors, and channels in biochemical assays and against a panel of non-kinase enzymes, quizartinib is not expected to have significant off-target effects.

The safety pharmacology of quizartinib was investigated in a series of in vitro and in vivo studies that mainly considered cardiovascular safety. Quizartinib inhibited the slowly activating component of delayed rectifier potassium currents (IKs) with a maximum inhibition of 67.5% at 2.9 µM. The maximum inhibition of the IKs by AC886 was 26.9% at 2.9 µM. Quizartinib and AC886 significantly inhibited human ether-à-go-go-related gene (hERG) currents by 16.4% and 12.0%, respectively, at a concentration of 3 μM. In a cardiovascular safety pharmacology study with telemetry conducted in cynomolgus monkeys, administration of quizartinib resulted in QT prolongation at doses approximately two times the maximum recommended human dose (MRHD) of 53 mg/day based on maximum concentration (C_max) and caused dose-related increases in systemic blood pressure. These results suggest that quizartinib and AC886 can induce blockade of hERG current and IKs, thereby causing QT prolongation by a decrease in the net repolarization currents.

Key non-clinical pharmacokinetic findings demonstrated that quizartinib exhibits low permeability and is a substrate of p-glycoprotein (P-gp), but not breast cancer resistance protein (BCRP), while its active metabolite AC886 is a BCRP substrate. In vivo studies showed dose-proportional pharmacokinetics at lower doses, with deviations at higher doses across species, and highlighted sex-related differences in bioavailability.

Quizartinib is widely distributed, with high concentrations in the intestines, eye uveal tract, and meninges, and with low brain penetration. Both compounds were 99% or more plasma protein bound. Metabolism is primarily cytochrome P450 (CYP)3A4/5-mediated, with rapid conversion to AC886. The main route of elimination is in the feces.

Drug interaction studies indicated that quizartinib did not significantly inhibit or induce major CYP enzymes, but, it inhibits uridine diphosphate (UDP)-glucuronosyltransferase 1-1 (UGT1A1) and BCRP.

The toxicology of quizartinib was assessed in repeat-dose studies in rats, dogs and monkeys for up to 13 weeks. The principal target organs of quizartinib-related toxicity were similar across these species and included the bone marrow, lymphoid organs, liver, and kidneys. Observations in the bone marrow included decreased red blood cells (RBC) and RBC parameters, decreased reticulocytes and white blood cells, correlating with hematopoietic hypocellularity. The majority of these microscopic changes were reversible or partially reversible. This toxicity was likely related to the targeted inhibition of FLT3, KIT and other kinases. Toxicity in the lymphoid organs manifested as decreased thymic organ weights and thymic lymphoid necrosis/atrophy, and splenic atrophy (not observed in chronic studies). These effects were mostly reversed following a 4-week recovery period. In the liver, observations included elevated aspartate aminotransferase (AST), alanine transaminase (ALT), and total bilirubin, histologic changes (single cell necrosis, centrilobular necrosis, hepatocellular vacuolation in the monkey and birefringent crystal deposition, sinusoidal cell activation, and hepatocellular vacuolation in the dog). The dog was considered the more sensitive species, though the relevance of these findings in humans is questionable, due to a unique quizartinib metabolite (morpholino oxidation product) observed in the dog. Findings in the kidneys included renal tubular birefringent crystal deposition and tubular basophilia (most prevalent in male rats) without abnormal clinical chemistry and renal microscopic changes. In dogs, renal tubular basophilia and non-birefringent renal tubular pigment deposits were also observed.

Mortalities occurred in monkeys in the chronic study at higher doses. Decreased food consumption, weight loss, and other clinical signs were also observed in all species, all of which were mostly reversible. Reproductive organ toxicity was observed in rats and monkeys. In rats, testicular seminiferous tubular degeneration, failure of sperm release, ovarian cysts, and non-reversible vaginal mucosal mucification was observed. In monkeys, germ cell depletion in the testes and atrophy of the uterus, ovary, and vagina was observed. These changes were reversible following a 4-week recovery period.

The no observed adverse effect level (NOAEL) in the 13-week studies was considered to be 3 mg/kg/day in the rat, 5 mg/kg/day in the dog, and 3 mg/kg/day in the monkey corresponding to 1.19, 0.39 and 0.07 times the MRHD of 53 mg daily based on area under the concentration-time curve (AUC) for rats, dogs, and monkeys, respectively.

In genotoxicity studies in vitro, quizartinib was mutagenic in a bacterial reverse mutation assay, but not in a mammalian cell mutation assay (mouse lymphoma thymidine kinase) or in a chromosome aberrations assay in human peripheral blood lymphocytes. In vivo, quizartinib was negative for genotoxicity in a single-dose bone marrow micronucleus assay and in the transgenic gene mutation assay (Big Blue rats); however, quizartinib produced equivocal results in a micronucleus assay following 28 days of administration.

In reproductive and developmental toxicity studies in rats, quizartinib was shown to be fetotoxic (lower fetal weights and effects on skeletal ossification) and teratogenic (high incidence of fetal malformation, mostly anasarca). Maternal toxicity, embryo-fetal lethality, lower fetal weight, and increased post-implantation loss were also observed. Based on maternal toxicity and fetal effects, the NOAEL was considered to be 6 and 2 mg/kg/day, corresponding to approximately 2.75 and 0.43 times the MRHD of 53 mg/day based on AUC, respectively.

In a rat juvenile toxicity study, quizartinib induced similar changes as those observed in adult rats, though juvenile animals appeared to have lower tolerance. The main target organs of toxicity were the bone marrow and male reproductive organs. The NOAEL for reproductive and developmental toxicity was considered to be 0.3 mg/kg/day, corresponding to 0.057 times the exposure at the MRHD of 53 mg/day.

In local tolerance studies in rabbits, quizartinib was considered a mild irritant of the ocular tissue and a slight irritant of the skin. Based on in vitro studies on 3T3 cells, quizartinib was considered to have a low potential for phototoxicity.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Vanflyta. In view of the intended use of Vanflyta, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Product Monograph for Vanflyta, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Vanflyta has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 60 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

Additionally, none of the excipients used in the formulation of Vanflyta is of human or animal origin.