Regulatory Decision Summary for Zykadia

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

ceritinib

Therapeutic area:

Antineoplastic Agents

Type of submission:

Supplement to a New Drug Submission

Control number:

205116
What was the purpose of this submission?

 

This Supplemental New Drug Submission (SNDS) was filed to revise the indication for Zykadia to include first-line treatment based on results of a phase III clinical study in previously untreated adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer.

 

Why was the decision issued?

 

In this submission, Zykadia (ceritinib) is recommended as monotherapy for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amendable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) based on results of study A2301 (ASCEND-4), a global multicentre, randomized, open-label Phase III study comparing Zykadia at a dose of 750 mg taken orally daily with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC 5-6) for 4 cycles followed by pemetrexed monotherapy maintenance in patients without disease progression in previously untreated adult patients with ALK-positive locally advanced or metastatic NSCLC. The control chemotherapy was considered standard of the care for the disease at the time of trial initiation.

The study met its primary objective, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) as assessed by a Blinded Independent Review Committee (BIRC) in the Zykadia arm compared with the chemotherapy arm [hazard ratio (HR) 0.55; 95% confidence interval (CI): 0.42, 0.73; p < 0.001)]. Median PFS was 16.6 months (95% CI: 12.6, 27.2) in the Zykadia arm compared with 8.1 months (95% CI: 5.8, 11.1) in the chemotherapy arm. The objective response rate (ORR) assessed by BIRC was higher in the Zykadia arm (72.5%; 95% CI: 65.5, 78.7) versus chemotherapy arm (26.7%; 95% CI: 20.5, 33.7). The overall survival (OS) was not mature at the time of data cut off; median OS was not estimable (NE) in the Zykadia arm (95% CI: 29.3, NE) and 26.2 months (95% CI: 22.8, NE) in the chemotherapy arm (HR 0.73, 95% CI: 0.5, 1.08). Patients with asymptomatic and neurologically stable central nervous system (CNS) metastases were enrolled in the study. CNS ORR based on BIRC assessment were 72.7% (95% CI: 49.8, 89.3) and 27.3% (95% CI: 10.7, 50.2) among patients with measurable lesions. Median PFS in patients with CNS metastases were 10.7 and 6.7 months in the Zykadia and chemotherapy arms, respectively.

Safety findings of the ASCEND-4 study were generally consistent with the known safety profile of Zykadia in adult patients with ALK-positive advanced NSCLC. Briefly, the most frequently reported adverse events (AEs) in the Zykadia arm (in ≥ 20% of patients) were diarrhea, nausea, vomiting, increased alanine transaminase (ALT), increased aspartate transaminase (AST), increased gamma-glutamyl transferase (GGT), increased blood alkaline phosphatase (ALP), decreased appetite, and fatigue. AEs that required dose interruption or adjustment were 80.4% and 44.6% in the Zykadia and chemotherapy groups, respectively. The most frequently reported AEs that led to dose interruption or adjustment in the Zykadia arm (≥ 10%) were increased ALT, increased AST, vomiting, increased blood creatinine, increased GGT, diarrhea and nausea. AEs leading to treatment discontinuation were reported in 11.1% of patients in the Zykadia arm and 16.6% in the chemotherapy arm. The most frequently reported AEs (in ≥ 1% of the patients) leading to Zykadia discontinuation were increased blood creatinine, increased lipase and increased amylase. On-treatment deaths were reported in 11 patients (5.8%) in the Zykadia arm, 7 due to disease progression and 4 due to AEs (one each for myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause). These safety findings were adequately described in the Product Monograph.

Based on the results of the ASCEND-4 study, the benefit-harm-uncertainty profile for Zykadia is considered favorable for the first-line treatment of patients with ALK-positive, locally advanced (not amenable for curative therapy) or metastatic NSCLC.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.