Summary Basis of Decision for Zykadia
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Zykadia is located below.
Recent Activity for Zykadia
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Zykadia
Updated:
The following table describes post-authorization activity for Zykadia, a product which contains the medicinal ingredient ceritinib. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02436779 - 150 mg ceritinib, capsule, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 215945 | 2018-05-01 | Issued NOC2018-12-06 | Submission filed as a Level I - Supplement to update the PM with a new dosing regimen. The safety and efficacy profile of the new dosing regimen (450 mg with food) is considered favourable. The requested changes to the PM to revise the recommended dose and instructions for administration with respect to food are considered to be supported. An NOC was issued. |
| NC # 220615 | 2018-10-01 | Cancellation Letter Received2018-10-26 | Submission filed as a Level II (90 day) Notifiable Change to update the PM with new information. The proposed revisions exceeded the scope of a Notifiable Change. The submission was therefore cancelled administratively by the sponsor so as to be filed as a Supplemental New Drug Submission. |
| SNDS # 205116 | 2017-05-04 | Issued NOC2018-06-06 | Submission filed as a Level I - Supplement for new indication 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. Regulatory Decision Summary published. |
| SNDS # 207972 | 2017-07-27 | Issued NOC under NOC/c Guidance2018-05-29 | Submission filed as a Level I - Supplement to update the PM with results from a dedicated hepatic impairment study. With this new information, the overall benefit-uncertainty-harm assessment remains favourable for Zykadia when used as recommended for the authorized indication. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information of the PM. The submission was reviewed and considered acceptable. An NOC under NOC/c Guidance was issued. |
| SNDS # 204766 | 2017-04-13 | Issued NOC under NOC/c Guidance2018-03-12 | Submission filed as a Level I - Supplement to update the PM based on new pharmacokinetic analyses. As a result of the SNDS, modifications were made to the Drug Interactions section of the PM. Appropriate changes were made to the PM. The data were reviewed and considered acceptable. The benefit-risk ratio of the product is considered to remain favourable. An NOC under NOC/c Guidance was issued. |
| SNDS-C # 202746 | 2017-02-10 | Issued NOC under NOC/c Guidance2018-02-05 | Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. This submission provided an interim report of the confirmatory Phase III study CLDK378A2303. The efficacy data from the Phase III randomized study confirmed the clinical benefit of Zykadia. No new unexpected safety signals were reported. With this new information, the overall benefit-uncertainty-harm assessment remains favourable for Zykadia when used as recommended for the authorized indication. The updated Product Monograph provides relevant information for the safe and effective use of Zykadia. An NOC under the NOC/c Guidance was issued. |
| PSUR-C # 207184 | 2017-07-05 | Filed2018-01-10 | Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2016-10-29 to 2017-04-28. No further action was required. |
| PSUR-C # 201663 | 2017-01-04 | Filed2018-01-05 | Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2016-04-29 to 2016-10-28. The information was reviewed and found acceptable. |
| SNDS # 205308 | 2017-05-04 | Cancellation Letter Received2017-11-23 | Submission filed as a Level I - Supplement to update the PM with results from Study CLDK378A2112. The sponsor cancelled the submission before it was reviewed. |
| SNDS-C # 201361 | 2016-12-20 | Issued NOC under NOC/c Guidance2017-10-20 | Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. This submission provided the final clinical study report for the confirmatory trial, Study CLDK378X2101. The safety profile of Zykadia based on the final analysis of this pivotal Phase I study is still consistent with that of the interim analysis and no new safety signal was identified. The overall benefit-harm-uncertainty profile therefore remains unchanged and favourable. An NOC under the NOC/c Guidance was issued. |
| SNDS # 203896 | 2017-03-20 | Cancellation Letter Received2017-04-12 | Submission filed as a Level I - Supplement to update the PM with results from Study CLDK378A2301. The sponsor cancelled the submission before it was reviewed. |
| PSUR-C # 192873 | 2016-03-01 | Filed2017-02-02 | Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2015-04-29 to 2015-10-28. The information was reviewed and found acceptable. |
| NC # 194492 | 2016-04-27 | Issued No Objection Letter2016-09-01 | Submission filed as a Level II (120 day) Notifiable Change to update the Product Monograph with information regarding a drug-drug interaction between Zykadia and gastric acid reducing agents. As a result of the NC, additions were made to the Drug Interactions section of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| SNDS-C # 185683 | 2015-06-29 | Issued NOC under NOC/c Guidance2016-05-04 | Submission filed as a Level I - Supplement to update the overall safety information of the Product Monograph (PM) based on pooled safety data from four ongoing clinical studies. No new safety information was identified from the four ongoing clinical studies and minor revisions were made to the following sections of the PM: Warnings and Precautions, Adverse Reactions and Part III: Patient Medication Information. The benefit-harm-uncertainty profile for Zykadia remains positive when used for its approved indication. |
| NC # 183754 | 2015-04-15 | Issued No Objection Letter2015-07-22 | Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) with safety information pertaining to pancreatic toxicity and hepatotoxicity. As a result of the Notifiable Change (NC), changes were made to the Warnings and Precautions and Dosing and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 184660 | 2015-05-20 | Cancellation Letter received2015-06-11 | Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update information in the Product Monograph (PM). A Screening Deficiency Notice was issued, as many of the proposed revisions in the Product Monograph exceeded the scope of a Notifiable Change. The submission was therefore cancelled administratively by the sponsor, so as to be filed as a Supplemental New Drug Submission. |
| Drug product (DIN 02436779) market notification | Not applicable | Date of first sale:2015-04-29 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 175702 | 2014-06-16 | Issued NOC2015-03-27 | Notice of Compliance issued for New Drug Submission under the NOC/c Guidance. |
Summary Basis of Decision (SBD) for Zykadia
Date SBD issued: 2015-06-17
The following information relates to the new drug submission for Zykadia.
Ceritinib, 150 mg, tablets, oral
Drug Identification Number (DIN):
- 02436779
Novartis Pharmaceuticals Canada Inc.
New Drug Submission Control Number: 175702
On March 27, 2015, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Novartis Pharmaceuticals Canada Inc. for the drug product Zykadia. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Zykadia is favourable as monotherapy for use in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to crizotinib.
1 What was approved?
Zykadia, a protein kinase inhibitor, was authorized as monotherapy for use in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to crizotinib.
Marketing authorization with conditions was based on a primary efficacy endpoint of overall response rate (ORR) as well as duration of response in clinical Study CLDK378X2101, based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST). There are no available data demonstrating improvement in survival or quality of life with Zykadia.
The safety and efficacy of Zykadia have not been established in pediatric patients (<18 years of age).
Of the 255 patients in the pivotal trial treated at a dose of 750 mg, 40 (15.7%) were 65 years or older. Although, no overall differences in safety or efficacy were observed between younger (<65 years) and older patients, an insufficient number of patients ≥65 years old were enrolled in the clinical study to rule out the risk of reduced efficacy or increased toxicity.
Zykadia is contraindicated for patients with a known hypersensitivity to the active substance, ceritinib, or to any ingredient in the formulation. Zykadia is also contraindicated for patients with congenital long QT syndrome or with a persistent Fridericia-corrected electrocardiogram interval (QTcF) of >500 msec. Zykadia was approved for use under the conditions stated in the Zykadia Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Zykadia (150 mg ceritinib) is presented as a capsule. In addition to the medicinal ingredient, ceritinib, the capsule also contains black iron oxide, colloidal anhydrous silica; gelatin; indigotine; L-hydroxypropylcellulose; magnesium stearate; microcrystalline cellulose; sodium starch glycolate, and titanium dioxide.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Zykadia Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Zykadia approved?
Health Canada considers that the benefit/risk profile of Zykadia is favourable as monotherapy for use in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to crizotinib. Zykadia was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.
Marketing authorization with conditions was based on a primary efficacy endpoint of overall response rate (ORR) as well as duration of response (DOR) in clinical Study CLDK378X2101, based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. There are no available data demonstrating improvement in survival or quality of life with Zykadia.
Advanced or metastatic NSCLC is an incurable disease. A key oncogenic driver of 2-7% of NSCLCs is genetic abnormalities in the ALK gene. ALK-positive NSCLC affects approximately 400 to 1,500 Canadians per year. In Canada, there is one available ALK inhibitor drug (crizotinib) that is authorized for use in NSCLC patients with ALK-positive disease. However, disease progression occurs for various reasons, including crizotinib resistance. Patients whose disease has progressed on crizotinib represent a population with an unmet medical need. Zykadia represents a new therapeutic option for these patients.
Zykadia has been shown to be efficacious in ALK-positive locally advanced or metastatic NSCLC patients that have progressed on crizotinib. The investigator-determined ORR was 55% and although most responses were partial responses, the data were considered promising, given that the responses occurred in approximately half of the patients that were heavily pretreated (chemotherapy) and crizotinib resistant. The data were also supported by a Blinded Independent Review Committee (BIRC) assessment which determined that the ORR was 44%. The median time to response in this study was approximately 6 weeks with a median DOR of 7 months. Although these are preliminary results based on a single-arm study with no control arm, the ORR and DOR are promising and are expected to be confirmed by data from the Phase III randomized study CLDK378A2303. The anticipated study completion date is December 2017 with the final clinical study report to be submitted to Health Canada in the third quarter of 2018.
The efficacy results were coupled with a tolerable and manageable safety profile. The most common adverse drug reactions (ADRs) occurring in ≥10% of patients were: diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%), fatigue (52%), increased alanine aminotransferase (ALT, 43%), decreased appetite (34%), increased aspartate aminotransferase (AST, 31%), constipation (29%), esophageal disorder (16%), rash (16%), and increased blood creatinine (15%). The Grade 3-4 ADRs with an incidence of ≥1% were anemia, hypophosphatemia, pneumonitis, nausea, vomiting, abdominal pain, fatigue, increased ALT, increased AST, diarrhea, increased lipase, prolonged electrocardiogram QT, and hyperglycemia. Most of these ADRs, although significant, were predominantly mitigated in the pivotal study by dose reductions/interruptions and are labelled throughout the Zykadia Product Monograph in the Warnings and Precautions as well as the Adverse Reactions sections. Additionally, to ensure safe and effective drug use and to enhance communication of toxicity to prescribers, the following safety risks from the pivotal study are labelled in the Serious Warnings and Precautions box: QTc interval prolongation, interstitial lung disease/pneumonitis, hepatotoxicity, and gastrointestinal toxicity. The boxed labelling also highlights that Zykadia has not been studied in patients with hepatic or severe renal impairment.
The non-clinical review revealed that Zykadia was genotoxic and led to embryofetal toxicity (visceral anomalies and skeletal variations) in both rat and rabbit reproductive and development studies. These findings are labelled in the Warnings and Precautions section. Specifically, the Zykadia Product Monograph provides the recommendation that because the potential risk of teratogenicity in humans is unknown; Zykadia should not be given to pregnant women, unless the potential benefit to the mother outweighs the potential risk to the fetus. Health Canada considers this to be an acceptable approach to risk mitigation in the patient population included in the indication (patients with advanced or metastatic NSCLC). The remainder of the non-clinical information was generally consistent with the clinical safety profile.
The Chemistry and Manufacturing review noted the submission data were considered accurate and complete with regards to shelf life, accuracy of pharmaceutical information and certified product information document.
A Risk Management Plan (RMP) for Zykadia was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
In summary, Zykadia is considered to have a favourable benefit-risk profile under the proposed conditions of use. The ORR and the DOR demonstrated in the Zykadia single-arm study are considered to be promising in a patient population with ALK-positive locally advanced or metastatic NSCLC that has progressed on crizotinib. Additionally, the efficacy is coupled with a tolerable and manageable safety profile which is well described in the Zykadia Product Monograph. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Zykadia will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available. For the list of the post-approval commitments, refer to the section What follow-up measures will the company take?
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Zykadia?
The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission (NDS) for Zykadia. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness that the drug has the potential to provide effective treatment of a disease or condition for which no drug is presently marketed in Canada.
Submission Milestones: Zykadia
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2014-01-21 |
| Submission filed: | 2014-06-16 |
| Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2014-06-23 |
| Screening Acceptance Letter issued: | 2014-07-17 |
| Quality Evaluation complete: | 2015-01-27 |
| Clinical Evaluation complete: | 2015-01-27 |
| Biostatistics Evaluation complete: | 2014-10-22 |
| Labelling Review complete: | 2015-01-28 |
| Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: | 2015-01-30 |
| Response filed (Letter of Undertaking): | 2015-03-20 |
| Notice of Compliance (NOC) issued by Director General under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2015-03-27 |
The Canadian regulatory decision on the non-clinical and clinical review of Zykadia was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Zykadia, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) providing:
1. Confirmatory Studies:
Final Clinical Study Reports (CSRs) from the following confirmatory studies will be submitted to Health Canada to support the efficacy and safety of Zykadia in patients previously treated with chemotherapy and crizotinib:
- Study CLDK378A2303 (Final CSR 3Q2018): titled "A Phase III multicentre, randomized study of oral Zykadia versus standard chemotherapy in adult patients with ALK-rearranged (ALK-positive) locally advanced or metastatic NSCLC who have been treated previously with one chemotherapy regimen (platinum doublet) and crizotinib."
Patients randomized to the reference chemotherapy treatment will be allowed to crossover to Zykadia treatment while being followed in the study after a Blinded Independent Review Committee has documented disease progression.
The CSR will include final Zykadia exposure-response analysis for progression free survival (PFS), overall response rate (ORR), overall survival (OS), and safety endpoints. - Study CLDK378X2101 (Final CSR 4Q2016): First-in-human, open-label, Phase I study of Zykadia conducted in 304 adult patients with advanced tumors confirmed to have genetic abnormalities in ALK.
- Study CLDK378X1101 (Final CSR 4Q2017): Phase I, open-label, dose-escalation and expansion study in Japanese patients with ALK-positive tumors.
2. Post Market Data:
- Annual developmental safety update reports (DSURs) and periodic safety update reports - confirmatory (PSUR-c's) should be provided to the Therapeutic Products Directorate in a manner deemed consistent with the current Notice of Compliance with Conditions (NOC/c) Guidance.
Additionally, the sponsor has agreed to provide the results of the following trials to Health Canada (which are not considered commitments as part of the NOC/c market authorization):
- Study CLDK378A2112 (Final CSR 3Q2017): A Phase I, multi-centre, randomized open label study to assess the systemic exposure and safety of 450 mg ceritinib taken with a low-fat meal and 600 mg ceritinib taken with a low-fat meal as compared with that of 750 mg ceritinib taken in the fasted state in adult patients with anaplastic lymphoma kinase (ALK) rearranged (ALK-positive) metastatic non-small cell lung cancer (NSCLC).
- Study CLDK378A2110 (Final CSR 2Q2016): A Phase I, open label, multi-centre, single dose study to evaluate the pharmacokinetics of ceritinib in subjects with hepatic impairment compared to subjects with normal hepatic function.
- Study CLDK378A2103 (Final CSR 1Q2017): A Phase I, multi-centre, open label, drug-drug interaction study to assess the effect of ceritinib on the pharmacokinetics of warfarin and midazolam administered as a two-drug cocktail in patients with ALK-positive advanced tumors including NSCLC.
- Study CLDK378A2113 (Final CSR 1Q2016): A Phase I, open-label, two-period, single-centre study to assess the effect of esomeprazole (proton pump inhibitor) on the pharmacokinetics of ceritinib in healthy subjects.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Approximately 2-7% of non-small cell lung cancers (NSCLCs) have genetic abnormalities in the anaplastic lymphoma kinase (ALK) gene. Ceritinib, the medicinal ingredient of Zykadia, is a selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein signal transducer and activator of transcription 3 (STAT3), and proliferation of ALK-dependent cancer cells both in vitro and in vivo.
The absorption, distribution, metabolism, and excretion (ADME) of ceritinib in humans were characterized in an open-label, single centre, Phase I study after a single oral administration of 750 mg of ceritinib in healthy male subjects.
The proposed dosing is 750 mg (5 × 150 mg) oral capsules taken daily on an empty stomach. The time to maximum plasma concentration (T-max) following the administration of the proposed dose is at about 4-6 hrs, where absolute bioavailability has not been established. In the plasma, approximately 82% of the dose is the parent drug. Ceritinib is highly bound to protein (97%) and is extensively distributed in tissues [volume of distribution (Vd) approximately 4,230 L] with slight preferential distribution to red blood cells. Ceritinib is a substrate of P-glycoprotein (P-gp) and is mainly metabolized by cytochrome P450 (CYP) 3A. The half-life is about 41 hrs and the clearance is 88.5 L/h for a single dose and 33.2 L/h at steady state. Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.
In vitro drug-drug interaction (DDI) studies with human-only biomaterials demonstrated that ceritinib will likely inhibit the in vivo clearance of drugs metabolized by CYP2A6, CYP2C9, CYP3A (reversible and time-dependent), and possibly CYP2E1 but not CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6. The sponsor is not planning to investigate the clinical DDI of ceritinib with CYP2A6 and CYP2E1, therefore a detailed description of the in vitro studies has been included in the Product Monograph to mitigate possible risks.
A food effect study indicated that even a low-fat meal can increase the exposure of ceritinib. Zykadia must be taken on an empty stomach. No food should be eaten for at least two hours before and two hours after the dose of Zykadia is taken. The recommendations highlight that food significantly alters the pharmacokinetics of the drug.
DDI studies demonstrated that strong CYP3A inhibitors/inducers co-administered with ceritinib significantly impact the exposure of the drug. The current Product Monograph reflects these study observations and recommends avoidance of co-administration of Zykadia with strong CYP3A inducers or inhibitors.
Overall, the Zykadia clinical pharmacology dataset is considered acceptable to support this New Drug Submission (NDS). Key clinical pharmacology findings and related risks are properly labelled in the final Zykadia Product Monograph. The clinical pharmacological data support the use of Zykadia for the specified indication.
For further details, please refer to the Zykadia Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Zykadia (ceritinib) in the treatment of patients with ALK-positive NSCLC was investigated in a Phase I, multi-centre, open-label study (Study CLDK378X2101) which included a dose-escalation phase and an expansion phase at the recommended dose of 750 mg. All patients enrolled in the study had locally advanced or metastatic malignancy that had progressed despite standard therapy and all patients were previously tested for ALK abnormalities. Prior ALK inhibitor therapy was permitted. Two-hundred and ninety of the 304 patients enrolled in the study were ALK-positive NSCLC patients. At the time of the data cut-off, a total of 246 ALK-positive NSCLC patients were treated with Zykadia at a dose of 750 mg, of which 163 had received prior treatment with crizotinib. Of these 163 patients, 3 had locally advanced disease, 157 had metastatic disease, and for 3 patients, data on disease stage were missing.
The primary efficacy endpoints were overall response rate (ORR) and duration of response (DOR) based on investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 in patients who were treated with a Zykadia dose of 750 mg. An additional evaluation of ORR and DOR was also performed based on a central Blinded Independent Review Committee (BIRC) assessment according to RECIST 1.0.
Of the 163 ALK-positive NSCLC patients who had received prior treatment with crizotinib, 54.6% [95% confidence interval (CI): 46.6, 62.4] of patients had a tumour response that was confirmed at least 4 weeks after the initial assessment. The median time to the first objective tumour response (complete response or partial response) that was subsequently confirmed was 6.1 weeks. The median DOR in patients who responded was 7.4 months (95% CI: 5.4, 10.1). This was supported by BIRC assessment where the ORR was 43.6% (95% CI: 35.8, 51.5) with a median time to response (6 weeks) and a DOR (7.1 months; 95% CI: 5.6, not estimable) that was similar to that observed by the investigators.
The lack of a Phase III study limits the ability to assess the true clinical efficacy of Zykadia. For example, there are no data demonstrating an overall survival, progression-free survival, or quality of life benefit in this patient population as compared to control; however, results are expected in the third quarter of 2018 from the clinical study report for Study CLDK378A2303, A Phase III, Multi-centre, Randomized, Open-label Study Oral Zykadia Versus Standard Chemotherapy in Adult Patients With ALK-rearranged (ALK-positive) Advanced NSCLC Who Have Been Treated Previously with Chemotherapy (Platinum Doublet) and Crizotinib. Further evaluation will then take place to confirm the clinical efficacy of Zykadia.
For more information, refer to the Zykadia Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The median exposure to Zykadia was 27 weeks (range: 0.4 to 82.3 weeks). The key adverse drug reactions (ADRs) were gastrointestinal toxicity (diarrhea, nausea, vomiting, abdominal pain) and hepatotoxicity (transaminase elevations) which occurred in >95% and >30% of patients, respectively. The most frequent adverse events reported in ≥10% of patients that led to dose reduction or interruption were alanine aminotransferase (ALT) increase (28.6%), nausea (19.6%), diarrhea (16.1%), aspartate aminotransferase (AST) increase (15.7%), and vomiting (15.7%). The Grade 3-4 ADRs with an incidence of ≥1% were anemia, hypophosphatemia, pneumonitis, nausea, vomiting, abdominal pain, fatigue, ALT increase, AST increase, diarrhea, lipase increase, electrocardiogram QT prolongation, and hyperglycemia. All of the above events including recommendations for their management are labelled in the Product Monograph.
Although the number of patients in the safety database is adequate [number (n), n = 255], patients that had a short duration of exposure (significantly under the median exposure of 27 weeks) may not sufficiently reflect the AEs associated with Zykadia. In addition, the absence of randomized controlled trials in this submission makes it difficult to distinguish AEs due to disease progression and those due to Zykadia. A Phase III randomized study (Study CLDK378A2303) is expected to allow for a comparison of safety and efficacy between Zykadia-treated and comparator drug-treated patient groups. Health Canada has requested the final clinical study report for Study CLDK378A2303 be submitted as a post-approval commitment.
The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Zykadia:
- QT interval prolongation;
- Interstitial Lung Disease/Pneumonitis, including fatal cases;
- Zykadia has not been studied in patients with hepatic impairment or severe renal impairment requiring peritoneal dialysis or hemodialysis;
- Hepatotoxicity; and
- Gastrointestinal toxicity.
For more information, refer to the Zykadia Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Ceritinib demonstrated selective inhibition of anaplastic lymphoma kinase (ALK), insulin receptor, insulin-like growth factor 1 receptor, and c-ros oncogene 1 (ROS1) in biochemical and cellular assays as well as anti-tumour activity in mice bearing xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)-ALK or nucleophosmin (NPM)-ALK tumours sensitive or resistant to crizotinib. Efficacy was dose-dependent and correlated with pharmacodynamic inhibition of ALK-fusion variants. In non-clinical pharmacokinetic and toxicology studies, ceritinib achieved sufficient oral exposure; was widely distributed; was metabolized by cytochrome P450 (CYP) 3A4/5; was primarily eliminated via fecal route with both gastrointestinal and biliary contribution; demonstrated embryo-fetal toxicity; was genotoxic; and demonstrated an acceptable toxicity profile in rats and monkeys that corresponded with clinical observations. In sum, in vitro and in vivo data suggest that ceritinib is adequately tolerated and selective against ALK fusion proteins, which results in anti-tumour efficacy.
For more information, refer to the Zykadia Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Zykadia has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months for Zykadia stored at less than 30°C is acceptable.
Proposed limits of drug-related impurities are considered adequately qualified [that is, within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies].
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
None of the excipients used in the manufacture of Zykadia are of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ZYKADIA | 02436779 | NOVARTIS PHARMACEUTICALS CANADA INC | CERITINIB 150 MG |