Summary Basis of Decision for Xospata

Clinical Pharmacology

Gilteritinib (the medicinal ingredient in Xospata) is an orally available small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3).

In patients with relapsed or refractory acute myeloid leukemia (R/R AML), peak plasma levels of gilteritinib were observed 4-6 hours after oral administration in the fasted state. Concomitant food intake delayed the absorption of gilteritinib, without affecting the extent of absorption. The estimated half life of gilteritinib is 113 hours, and its estimated apparent clearance is 14.85 L/hr. Steady-state plasma levels were observed within 15 days of dosing, with an approximate 10-fold accumulation.

Gilteritinib is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4, and is also a substrate of P-glycoprotein (P-gp). Therefore, concomitant use of Xospata with strong inducers or inhibitors of CYP 3A4 and/or P-gp can alter gilteritinib exposure. Additionally, in vitro data indicate that gilteritinib may reduce the effects of drugs that target the serotonin 5HT2B or sigma non-specific receptors.

Gilteritinib exhibits linear and approximately dose-proportional pharmacokinetics at doses ranging from 20 to 450 mg in patients with R/R AML. Dosing of 80 mg and above resulted in rapid and sustained inhibition of FLT3 phosphorylation (over 90%), as characterized by an ex vivo plasma inhibitory activity assay.

Gilteritinib is associated with a risk of QT prolongation, as a concentration-related increase in QT interval (using Fridericia's correction formula; QTcF) was observed in the 20 to 450 mg dose range.

The results of a dedicated hepatic impairment study and population pharmacokinetic analyses indicated that mild to moderate hepatic or renal impairment had no clinically meaningful effects on the pharmacokinetics of gilteritinib. The effects of severe hepatic or severe renal impairment are unknown.

Overall, the clinical pharmacology data support the use of Xospata for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Xospata was evaluated in the pivotal Phase III study, ADMIRAL, and in the supportive Phase I/II study, CHRYSALIS.

DMIRAL was an open-label, randomized study in 371 adult patients with R/R AML with a confirmed FLT3 mutation. Patients were randomized in a 2:1 ratio to receive either Xospata or one of the pre-selected salvage chemotherapies. Randomization was stratified based on patient response to prior AML treatment and pre-selected chemotherapy (i.e., high or low intensity).

The starting dose for patients receiving Xospata was 120 mg daily, until the patient experienced unacceptable toxicity or a lack of clinical benefit. Dose reductions were permitted to manage adverse reactions, and a dose increase to 200 mg was permitted for some patients in the absence of a response to the treatment.

The primary efficacy endpoint in the final analysis was overall survival. A significant increase in overall survival was observed in patients treated with Xospata compared with patients in the chemotherapy arm (hazard ratio [HR] 0.637, 95% confidence interval [CI] 0.490-0.830, p = 0.0004). The median overall survival was 9.3 months in patients who received Xospata and 5.6 months in patients in the chemotherapy arm.

Complete remission was a key secondary endpoint, achieved by 21.2% of patients who received Xospata and 10.5% of patients in the chemotherapy arm.

The observed treatment effect was generally consistent across all subgroups examined, except in patients who had an unfavourable cytogenetic risk status at baseline.

CHRYSALIS was a dose escalation study in adult patients with R/R AML with a FLT3 mutation, who had previously received one or more lines of treatment. The complete remission rates were 12.5% in the 120 mg cohort and 11.2% in the 200 mg cohort.

Indication

Health Canada approved the following indication for Xospata:

• Xospata is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation.
• A validated test is required to confirm the FLT3 mutation status of AML.

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

Clinical Safety

The clinical safety of Xospata was assessed in adult patients with R/R AML with a FLT3 mutation enrolled in several clinical studies, including the pivotal study, ADMIRAL. ADMIRAL and the supportive dose escalation study, CHRYSALIS, are described in the Clinical Efficacy section.

Xospata has a different safety profile compared with the salvage chemotherapies. The most frequently reported adverse reactions (in 20% of patients or higher) were increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), diarrhea, fatigue, nausea, cough, constipation, peripheral edema, dyspnea, headache, vomiting, increased blood alkaline phosphatase (ALP), and dizziness.

The most frequently observed serious adverse reactions were acute kidney injury (6.6%), diarrhea (4.7%), increased ALT (4.1%), dyspnea (3.4%), increased AST (3.1%), hypotension (2.8%), syncope (2.5%), and differentiation syndrome (2.2%). Three cases of adverse reactions had fatal outcomes: one case of congestive heart failure and two cases in which clinical symptoms were consistent with differentiation syndrome.

Post-baseline corrected QT (QTc) interval prolongation of any grade was observed in 8.8% of patients in clinical studies. A QT interval greater than 500 ms (using Fridericia's correction formula; QTcF) was reported in 1.3% of patients, and 6.6% of patients had an increase greater than 60 ms in QTcF relative to baseline values. Adverse events of pancreatitis and posterior reversible encephalopathy syndrome were observed in patients treated with Xospata.

Adverse reactions were generally manageable with close monitoring, modification of Xospata dosage, and/or treatment of symptoms.

The safety and efficacy data from the ADMIRAL and CHRYSALIS studies support a recommended dose of 120 mg daily. The sponsor proposed an increase in the daily dose from 120 mg to 200 mg in the absence of a response after four weeks of treatment. Although a dose increase to 200 mg was allowed in some patients in the pivotal ADMIRAL study, it is unclear whether the higher dose of 200 mg was associated with increased efficacy. However, dose escalation was associated with risks of increased QT prolongation and increased liver enzyme and creatinine phosphokinase levels. Additionally, there was a higher incidence of treatment discontinuation due to adverse events in the 200 mg cohort in the CHRYSALIS study, compared with the 120 mg cohort (45.6% and 17.4% of patients, respectively). Therefore, the available evidence does not support the dose increase.

Differentiation syndrome is highlighted in a Serious Warnings and Precautions box in the Xospata Product Monograph. Differentiation syndrome was observed in patients who received Xospata, and can be fatal if left untreated. Symptoms and clinical findings may include fever, dyspnea, pleural effusion, pericardial effusion, pulmonary infiltrate, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. In some cases, patients had concomitant acute febrile neutrophilic dermatosis. If differentiation syndrome is suspected, corticosteroid therapy and hemodynamic monitoring are recommended until symptoms resolve.

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