Regulatory Decision Summary for Xospata

The efficacy and safety of Xospata were assessed in a Phase III randomized pivotal study (ADMIRAL) comparing Xospata monotherapy at the dose of 120 mg daily with a salvage chemotherapy of investigators choice in 371 adult patients who had relapsed or refractory acute myeloid leukemia (R/R AML) with a FLT3 mutation.

At the pre-planned final analysis, the study met its primary efficacy endpoint and demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in the Xospata arm versus (vs) chemotherapy control arm (median OS: 9.3 vs 5.6 months; hazard ratio [HR] 0.637, 95% confidence interval [CI]: 0.490, 0.830; p = 0.0004). The HR indicates that there was a 36% decreased risk of death in patients receiving Xospata vs patients treated with salvage chemotherapies. Results of sensitivity and subgroup OS analyses were generally consistent, indicating that the OS results were robust. Complete remission (CR) rate was a key secondary endpoint and CR rate was numerically higher in the Xospata arm [21.1%, 95% CI: 16.1, 26.7] vs chemotherapy control arm (10.5%, 95% CI: 5.7, 17.3).

The safety of Xospata monotherapy was assessed in adult patients with FLT3 mutation-positive R/R AML treated with Xospata at 120 mg daily in clinical trials including the pivotal ADMIRAL study. Xospata demonstrated a different safety profile compared with salvage chemotherapies. The most frequent adverse reactions (≥ 20%) were alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, diarrhea, fatigue, nausea, cough, constipation, peripheral edema, dyspnea, headache, vomiting, blood alkaline phosphatase (ALP) increased and dizziness. The most frequent serious adverse reactions were acute kidney injury (6.6%), diarrhea (4.7%), ALT increased (4.1%), dyspnea (3.4%), AST increased (3.1%), hypotension (2.8%), syncope (2.5%) and differentiation syndrome (2.2%). Fatal adverse reactions included two cases with clinical symptoms consistent with differentiation syndrome and one case of congestive heart failure. A total of 8.8% patients had a post-baseline corrected QT interval (QTc) prolongation of any grade in clinical trials. Among these patients, 1.3% had a Fridericia-corrected QT interval (QTcF) greater than 500 msec and 6.6% had an increase from baseline QTcF greater than 60 msec. The adverse reactions were generally manageable with close monitoring, modification of Xospata dosage and/or symptomatic treatment. The adverse reactions are adequately described, and recommendations for monitoring and management are provided in the approved product monograph (PM). Based on non-clinical study findings, Xospata has the potential to cause fetal harm when administered to a pregnant woman. A Canadian Risk Management Plan (RMP) was submitted. The Marketed Health Products Directorate (MHPD) reviewed the plan and considered it acceptable.

The nonclinical pharmacodynamic data supported the proposed mode of action of gilteritinib. Given the intended use of gilteritinib in patients with advanced cancer, no nonclinical toxicological issues were identified that would preclude approval of this application. Appropriate warnings and precautionary measures are included in the Product Monograph to address the identified non-clinical risks. The clinical pharmacology development adequately characterised the pharmacokinetic profile of gilteritinib and its potential pharmaceutic interactions with other drugs.

The final labels, Patient Medication Information and Package Insert were reviewed and found acceptable.

In the context of R/R AML with a FLT3 mutation, the benefit-harm-uncertainty profile is considered favorable for Xospata.