Summary Basis of Decision for Tagrisso
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 Tagrisso is located below.
Recent Activity for Tagrisso
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 Tagrisso
Updated:
The following table describes post-authorization activity for Tagrisso, a product which contains the medicinal ingredient osimertinib mesylate. 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 list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number(s) (DINs):
- DIN 02456214 – 40 mg, osimertinib mesylate, tablet, oral
- DIN 02456222 – 80 mg, osimertinib mesylate, tablet, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 247767 | 2020-12-21 | Issued NOC2022-06-29 | Submission filed as a Level I – Supplement to add an alternate manufacturing site for the drug substance. The submission was reviewed and considered acceptable. An NOC was issued. |
| SNDS # 257918 | 2021-10-25 | Issued NOC2022-03-03 | Submission filed as a Level II – Supplement (Safety) to update the Product Monograph with new safety information, to fulfil a commitment made as per the provisions of the NOC/c Guidance, and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. An NOC was issued. |
| SNDS # 249994 | 2021-02-26 | Issued NOC2022-01-21 | Submission filed as a Level I – Supplement to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Contraindications, Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, Drug Interactions, Dosage and Administration, and Overdosage sections, and Part III: Patient Medication Information of the PM. An NOC was issued. |
| SNDS # 243288 | 2020-08-27 | Issued NOC2021-01-18 | Submission filed as a Level I – Supplement to add a new indication for Tagrisso. The indication authorized was for adjuvant therapy after tumour resection in patients with stage IB-IIIA non-small cell lung cancer whose tumours have epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 242157 | 2020-07-24 | Issued NOC2020-11-27 | Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section and Part III: Patient Medication Information of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 234607 | 2019-12-18 | Issued NOC2020-10-07 | Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, and Clinical Pharmacology sections of the PM. An NOC was issued. |
| NC # 234409 | 2019-12-12 | Issued NOL2020-03-16 | Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections and Part III: Patient Medication Information of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 219271 | 2018-09-10 | Issued NOC2019-08-07 | Submission filed as a Level I - Supplement to provide an update to the PM based on data from clinical pharmacology studies. As a result of the submission, the following sections of the PM were updated: Warnings and Precautions, Adverse Reactions, Drug Interactions, and Dosage and Administration. Corresponding changes were made to the PM Part III: Patient Medication Information. The benefit/risk profile for Tagrisso remains positive when used for its approved indication. The submission was reviewed and considered acceptable. An NOC was issued. |
| SNDS # 213719 | 2018-03-02 | Issued NOC2018-10-01 | Submission filed as a Level I - Supplement to add a new supplier of a starting material for the manufacture of the drug substance. There were no changes to the approved drug substance specifications. There were no changes to the quality of the drug product as a result. The information was reviewed and considered acceptable. An NOC was issued. |
| SNDS # 211762 | 2017-12-13 | Issued NOC2018-07-10 | Submission filed as a Level I – Supplement to add a new indication for Tagrisso. The indication authorized was for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer whose tumours have epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS-C # 203014 | 2017-02-17 | Issued NOC2018-01-19 | Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. This SNDS-C was submitted to provide the final study report for the confirmatory studies AURAex, AURA2, and AURA3 and to update the PM with the data from these studies. Based on these data, this submission also requested the removal of the conditions from the NOC for this indication. The data continues to support an acceptable safety profile for the use of Tagrisso, and together, the data support the favourable benefit/risk profile of Tagrisso for its approved indication. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-07-05. |
| PBRER-C # 203505 | 2017-03-03 | Filed2018-01-10 | Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #1 for the period 2015-11-13 to 2016-05-12 and PBRER-C #2 for the period 2016-05-13 to 2016-11-12. The information was reviewed and found acceptable. |
| SNDS # 205867 | 2017-06-02 | Issued NOC2017-12-22 | Submission filed as a Level I - Supplement to register a new supplier of a starting material for the manufacture of the drug substance. There were no changes to the approved drug substance specifications. There were no changes to the quality of the drug product as a result. The information was reviewed and considered acceptable. An NOC was issued. |
| SNDS # 199091 | 2016-10-07 | Issued NOC2017-03-03 | Submission filed as a Level I - Supplement to register a new supplier of a starting material for the manufacture of the drug substance. There were no changes to the approved drug substance specifications. There were no changes to the quality of the drug product as a result. The information was reviewed and considered acceptable. An NOC was issued. |
| Drug product (DINs 02456214, 02456222) market notification | Not applicable | Date of first sale:2016-07-19 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 188171 | 2015-10-01 | Issued NOC2016-07-05 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Tagrisso
Date SBD issued: 2016-09-22
The following information relates to the new drug submission for Tagrisso.
Osimertinib, as osimertinib mesylate, 40 mg and 80 mg , tablets, oral
Drug Identification Number (DIN):
- DIN 02456214 - 40 mg tablet
- DIN 02456222 - 80 mg tablet
AstraZeneca Canada Inc.
New Drug Submission Control Number: 188171
On July 5, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to AstraZeneca Canada Inc. for the drug product Tagrisso. 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 Tagrisso is favourable for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. A validated test is required to identify EGFR T790M mutation-positive status prior to treatment.
1 What was approved?
Tagrisso, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was authorized for the treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. A validated test is required to identify EGFR T790M mutation-positive status prior to treatment.
Tagrisso was authorized under the NOC/c Guidance based on promising evidence of clinical effectiveness, and the need for further follow-up data to confirm clinical benefit.
Marketing authorization with conditions is based on a primary efficacy endpoint of objective response rate (ORR) by blinded independent central review assessment using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in two Phase II, single-arm trials of 411 patients. Median duration of response (DoR), a secondary endpoint, has not been reached. There are no available data demonstrating improvement in overall survival with Tagrisso.
The safety and efficacy of Tagrisso in children below 18 years of age have not been established.
Tagrisso is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Tagrisso was approved for use under the conditions stated in the Tagrisso Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Tagrisso (40 mg and 80 mg osimertinib, as osimertinib mesylate) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains black iron oxide, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, macrogol 3350, polyvinyl alcohol, red iron oxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow iron oxide.
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 Tagrisso Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Tagrisso approved?
Health Canada considers that the benefit/risk profile of Tagrisso is favourable for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.
A validated test is required to identify EGFR T790M mutation-positive status prior to treatment.
Lung cancer is the leading cause of cancer death among both men and women. Patients who have EGFR sensitizing mutation (EGFRm) forms of NSCLC are particularly sensitive to treatment with currently available EGFR-TKI therapies, which block the cell signalling pathways implicated in tumor growth. However, tumours often develop resistance to EGFR-TKI therapies, leading to disease progression. This resistance is often caused by an additional mutation, T790M. Approved second-line treatment for these patients is doublet chemotherapy, but response rates are typically only 22%. Tagrisso is a new active substance developed to target EGFRm and T790M mutation-positive receptor forms of EGFR in patients with NSCLC.
Tagrisso has shown efficacy in patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR-TKI therapy. The marketing authorization with conditions was based on a primary efficacy endpoint, overall objective response rate (ORR) of 66.1% (mostly comprised of partial responses), as assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. These results were based on an interim analysis of pooled data (411 patients) from two pivotal Phase II, single-arm studies (AURAex and AURA2). The median duration of response had not been reached. There were no available data demonstrating improvement in overall survival. Although the data are immature (a short treatment duration and follow-up of approximately 8 months), the ORR and duration of response represent promising evidence of a clinically meaningful benefit of Tagrisso in controlling disease in this advanced cancer population. Confirmation of this benefit is expected with longer follow-up and more robust data from a Phase III randomized clinical trial (AURA3) comparing Tagrisso to platinum-based chemotherapy in the target population. The recommended 80 mg daily oral dose of Tagrisso is supported by pharmacokinetic, efficacy, and safety data provided in the submission. To manage toxicity, a dose reduction strategy using the 40 mg tablet is recommended.
Of the 411 patients in the Phase II AURA study population, 54.5% were <65 years of age, and 45.5% were ≥65 years of age. Patients ≥75 years of age comprised 13.1% of the overall population. Patients ≥65 years of age experienced more Grade ≥3 adverse reactions compared to patients <65 years (16.6% versus 7.6%, respectively). Exploratory subgroup analyses showed the highest frequency of Grade ≥3 adverse reactions in patients ≥75 years of age (24.1%), however, no clinically meaningful differences in efficacy or pharmacokinetics based on age were observed between these patients and younger patients. No starting dose adjustments are recommended in elderly patients.
In the Phase II studies, the most common adverse events in patients who received Tagrisso were diarrhea, nausea, constipation, stomatitis, skin effects (including rash, dry skin, pruritus and nail-related events such as paronychia), decreased appetite, cough, fatigue, back pain, decreased platelet count, and headache. These events are reflected in the Tagrisso Product Monograph.
Safety concerns such as interstitial lung disease (including fatal cases), QTcF interval prolongation, and left ventricular dysfunction and cardiomyopathy are included in a Serious Warnings and Precautions box in the Tagrisso Product Monograph, as they are potentially life-threatening and clinically significant. These risks are also managed via monitoring and dose adjustment recommendations.
Other important events in patients in the Phase II studies were ocular toxicity including keratitis (corneal inflammation) requiring dose interruption. Endophthalmitis/uveitis and blindness were reported in a small number of patients that received Tagrisso, but causality could not be determined. The risk of ocular toxicity is managed via labelling in the Warnings and Precautions and Adverse Reactions sections.
One serious adverse event of drug-induced liver injury (a potential Hy's Law case) was reported in one of the Phase II studies; however, due to confounding factors, causality could not be determined. As such, the labelling addresses the risk of hepatotoxicity associated with Tagrisso use.
Based on animal studies, Tagrisso was found to cause reproductive and fetal toxicity. Therefore, the labelling includes warnings advising female and male patients of the need to avoid pregnancy.
While the toxicities associated with Tagrisso can be serious, they were adequately managed in the Phase II studies by dose modification or reduction. Dose modification guidelines are included in the Tagrisso Product Monograph to manage these toxicities and the labelling also includes enhanced monitoring.
A validated test is required to identify EGFR T790M mutation-positive status prior to dosing. Locally validated tests and commercial kits are currently available in Canada to test for the EGFR T790M mutation, and all patients will have access to laboratories in Canada which use these validated tests.
A Risk Management Plan (RMP) for Tagrisso was submitted by AstraZeneca 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.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Tagrisso was accepted.
Overall, the therapeutic benefits seen in the two Phase II studies are promising and the benefits of Tagrisso therapy are considered to outweigh the potential risks. Patients with EGFR T790M mutation-positive advanced or metastatic NSCLC who progress on EGFR TKI therapy have a serious and life-threatening disease characterized by a low survival rate. Currently there are no market authorized therapies that target the acquired EGFR T790M TKI-resistance-conferring mutation. Although there are many safety concerns, the safety risks associated with Tagrisso are outweighed by the clinically meaningful benefit of Tagrisso in this patient population with limited treatment options, thereby fulfilling an unmet medical need. The identified safety issues can be managed through stringent labelling and enhanced monitoring. Appropriate warnings and precautions are in place in the Tagrisso Product Monograph to address the identified safety concerns.
Tagrisso 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 data to confirm the clinical benefit. Further evaluation will be undertaken when final confirmatory data from the pivotal Phase II AURA trials and the Phase III AURA3 trial are submitted.
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 Tagrisso?
The sponsor filed a request for Advanced Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission (NDS) for Tagrisso. An assessment was conducted and it was determined that there was promising evidence of clinical effectiveness that the drug has the potential to provide:
- Effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or
- A significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Tagrisso
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2015-07-07 |
| Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2015-08-14 |
| Submission filed: | 2015-10-01 |
| Screening | |
| Screening Acceptance Letter issued: | 2015-11-13 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2016-04-06 |
| Quality Evaluation complete: | 2016-05-10 |
| Clinical Evaluation complete: | 2016-05-27 |
| Initial Labelling Review complete: | 2016-05-27 |
| Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: | 2016-05-30 |
| Review of Response to NOC/c-QN: | |
| Response filed (Letter of Undertaking): | 2016-06-01 |
| Final Label review | 2016-06-30 |
| Clinical Evaluation complete: | 2016-06-30 |
| Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate, under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2016-07-05 |
The Canadian regulatory decision on the non-clinical and clinical review of Tagrisso was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Medicines Agency (EMA) and 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?
In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the final clinical study reports from the following post-authorization confirmatory trials:
- AURA3; a randomized Phase III study comparing Tagrisso 80 mg versus platinum-based doublet chemotherapy in patients with locally advanced or metastatic T790M mutation-positive non-small cell lung cancer (NSCLC) who progress on prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.
- AURAex; a Phase II single-arm, open-label, non-randomized study extension to AURA in patients with locally advanced or metastatic T790M mutation-positive NSCLC who progress on prior EGFR TKI.
- AURA2; a Phase II single-arm, open-label, non-randomized study to replicate the efficacy and safety data observed in the AURAex study.
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, Part III: Consumer Information/Patient Medication Information, Qualifying Notice, and Dear Healthcare 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
Tagrisso is a tyrosine kinase inhibitor (TKI). It is a selective and irreversible inhibitor of both Epidermal Growth Factor Receptor (EGFR) sensitizing mutations (EGFRm) and T790M resistance mutation (T790M). Tagrisso was granted Acceptance of Advanced Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR TKI therapy.
The major pharmacokinetic (PK) aspects of absorption, distribution, metabolism and elimination of Tagrisso have been well characterized in patients and healthy volunteers. Overall, the PK data support the recommended starting dose of 80 mg daily Tagrisso which also allows prescribers to manage toxicity via dose reduction with the 40 mg tablet.
Clinical studies with Tagrisso excluded patients with severely impaired renal or hepatic function. In a PK analysis of patients, mild hepatic impairment had no impact on the apparent clearance of Tagrisso, as exposures were similar to that in patients with normal hepatic function. Since an appropriate dose of Tagrisso in patients with moderate and severe hepatic impairment is not established, and given that Tagrisso is eliminated via hepatic metabolism, the labelling recommends exercising caution when administering Tagrisso to patients with moderate or severe hepatic impairment.
A formal clinical study to investigate the impact of renal impairment on Tagrisso exposure has not been performed. However, based on population PK analysis in patients with mild and moderate renal impairment versus normal renal function, Tagrisso exposures were similar. Limited data exists for patients with severe renal impairment. There is no PK data in patients with end stage renal disease. Because the safety and efficacy are not established in patients with end-stage renal disease or patients on dialysis, the labelling recommends exercising caution when treating these patients.
Overall, the data from the submitted clinical pharmacology studies are considered sufficient to support the marketing authorization of Tagrisso for the specified indication.
For further details, please refer to the Tagrisso Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Tagrisso 80 mg in the treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who progressed on or after EGFR TKI therapy was investigated in two pivotal Phase II, multicentre, single-arm, open-label clinical studies, AURAex (Phase II Extension cohort of 201 patients) and AURA2 (210 patients). Prior to dosing, all patients were required to have EGFR T790M mutation-positive NSCLC, determined using an investigational use version of the tissue-based cobas EGFR Mutation Test (CE-IVD) performed in a central laboratory.
The use of Tagrisso was first investigated in a Phase I, multicentre, single-arm, open-label, dose-escalation and expansion study (AURA) including 271 pre-treated patients with locally advanced or metastatic NSCLC across multiple dose expansion cohorts. The Phase II studies were initiated following the positive objective response rate (ORR) in the 80 mg dose level cohort of 63 patients with T790M mutation-positive NSCLC in this study.
The primary efficacy endpoint was objective response rate (ORR) based on blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Secondary efficacy outcomes included duration of response (DoR), disease control rate (DCR), best change from baseline in size of target lesion (that is [i.e.], tumour shrinkage), progression-free survival (PFS), and overall survival.
The clinical efficacy was assessed from interim results of the two pivotal Phase II studies (AURAex and AURA2). The interim data cut-off date of May 1, 2015 for AURAex was based on a median follow-up of approximately 8 months. The BICR-assessed ORR was 61.3% (95% confidence interval [CI]: 54.2% to 68.1%) based on 122/199 evaluable-for-response patients. All were partial responses. In AURA2 at the same data cut-off date, the confirmed ORR by BICR was 70.9% (95% CI: 64.0% to 77.1%) based on 141/199 evaluable-for-response patients. Most patients had confirmed partial responses, with only 2 confirmed complete responses. The clinical benefit of Tagrisso was demonstrated based on pooled AURA Phase II data (AURA2 and AURAex; number of patients [n] = 411) whereby the ORR was 66.1% (95% CI: 61.2% to 70.7%) and the median DoR was not calculable.
Limitations of these Phase II data include immature survival data (only 13.9% deaths in AURAex and 11.4% in AURA2), short treatment duration (median 7.4 months for AURA2 and 8.2 months for AURAex), and short follow-up of approximately 8 months. AURAex and AURA2 are single-arm studies with no comparator, and the small sample size limits conclusions with regard to exploratory subgroup analyses. At the data cut-off, no overall survival benefit was demonstrated.
Subgroup analyses of the pooled Phase II data showed numerical, but not statistically significant, differences in ORR among the categories within some subgroups based on ethnicity, EGFR mutation status, brain metastases status at entry, time since last treatment prior to first dose, and region. While the ORR was consistent across the subgroups and with the overall ORR, these findings were inconclusive since there were no sample size pre-estimates in the subgroup analyses.
The Phase I dose-expansion study (AURA) supported the findings from the Phase II AURA studies. In a subset of 63 patients with confirmed T790M-positive NSCLC and dosed at 80 mg Tagrisso, the ORR was 61.7%. The median follow-up was 8.2 months. The ORR in T790M mutation-negative patients who received an 80 mg dose was 24.1%. Due to the limitations of the study design with small sample size and lack of comparator, these findings were inconclusive but did identify the issue regarding specificity and sensitivity of the EGFR T790M mutation test.
The EGFR T790M mutation-positive status must be confirmed in tumour specimens prior to dosing. In the AURA Phase II studies, an investigational use version of the tissue-based cobas EGFR Mutation Test was used to select patients with EGFR T790M mutation-positive status. This test is not approved in Canada. AstraZeneca Canada Inc. has confirmed that locally validated tests and commercial kits are currently available in Canada to test for the EGFR T790M mutation, and that all patients will have access to laboratories in Canada which use these validated tests. The sensitivity and specificity of these tests is considered to be acceptable for use in the context of preselecting patients who are likely to benefit from treatment with Tagrisso.
Overall, the efficacy data presented are promising. The product 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 data to confirm the clinical benefit. Further evaluation will be undertaken when the requested confirmatory trials are submitted.
For more information, refer to the Tagrisso Product Monograph, approved by Health Canada and available through the Drug Product Database.
Indication
The New Drug Submission for Tagrisso was filed seeking the following indication:
- Tagrisso (osimertinib) is indicated for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.
In order to preselect patients that may benefit from Tagrisso therapy, Health Canada recommended the following indication which states that NSCLC patients must be identified as having EGFR T790M mutation-positive status using a validated test.
- Tagrisso (osimertinib) is indicated for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. A validated test is required to identify EGFR T790M mutation-positive status.
Clinical Safety
The clinical safety of Tagrisso was assessed from interim results of the two pivotal AURA Phase II studies (AURAex and AURA2, see Clinical Efficacy section) which enrolled 411 patients with advanced or metastatic NSCLC with EGFR T790M mutation-positive tumours. Patients received Tagrisso 80 mg tablet daily until progression or until treatment discontinuation criteria were met. Limitations of these Phase II data include a short treatment duration (median 7.4 months, range 0.03 months to 10.61 months for AURA2; and a median 8.2 months, range 0.1 month to 11.6 months for AURAex), and short follow-up of approximately 8 months.
Fatal adverse events (AEs) were reported in 13 of 411 patients (3.2%), mainly due to pneumonia, interstitial lung disease and respiratory failure, with others including pneumonitis, bacterial urinary tract infection, cerebral hemorrhage, cerebrovascular accident, congestive cardiac failure, and liver disorder.
Serious adverse events (SAEs) were reported in 20.2% (83/411) of patients receiving Tagrisso in the AURA Phase II studies. The most commonly reported SAEs were pneumonia, pulmonary embolism, interstitial lung disease (ILD) and pneumonitis. Uncommon SAEs included anemia, dyspnea, influenza, cerebral hemorrhage, cerebral infarction, cerebrovascular accident, deep vein thrombosis, fatigue, pleural effusion, aspiration pneumonia, respiratory failure, supraventricular tachycardia, thrombocytopenia, urinary tract infection, and abdominal pain.
The most commonly reported AEs in the AURA Phase II studies were diarrhea (42.3%), rash-related events (41.4%), dry skin-related events (30.9%), nail effects including paronychia (25.1%), nausea (16.8%), decreased appetite (15.8%), constipation (15.1%), cough (13.9%), fatigue (13.9%), pruritus (13.9%), back pain (12.7%), stomatitis (11.9%), decreased platelet count (11.4%), and headache (10.2%).
Other important commonly reported AEs (≥1% to <10%) include vomiting, dyspnea, arthralgia, peripheral edema, asthenia, decreased white blood cell count, dermatitis acneiform, increased alanine aminotransferase, increased aspartate aminotransferase, decreased neutrophil count, dry eye, maculo-papular rash, dizziness, dry mouth, neutropenia, electrocardiogram QT prolonged, myalgia, increased blood creatinine, conjunctivitis, leukopenia, blurred vision, epistaxis, increased blood alkaline phosphatase, decreased weight, hypocalcemia, hyponatremia, peripheral neuropathy, non-cardiac chest pain, hypertension, hyperkalemia/hypokalemia, hypoalbuminemia, hypomagnesemia, parasthesia, cataract, pleural effusion, skin exfoliation, increased blood bilirubin, hypotension, palmar-plantar erythrodysesthesia (hand-foot syndrome), hypophosphatemia, conjunctival hemorrhage, and reduced visual acuity.
Discontinuation of therapy due to AEs occurred in 5.6% of the patients treated with Tagrisso, with the most common events being ILD and pneumonia. Approximately 30% of the patients required dose modification mostly due to AEs, including approximately 4% who required a dose reduction. While the toxicities associated with Tagrisso were substantial, they were adequately managed in the Phase II studies by dose modification or interruption.
Exposure-response analysis suggested that the probability of rash and diarrhea increased with Tagrisso exposure; however, with regard to the relationship between exposure and risk of ILD, the results were inconclusive. Due to the seriousness of ILD-related events, this risk is prominently identified in the Serious Warnings and Precautions box in the Tagrisso Product Monograph, along with the risks of QTc interval prolongation, cardiomyopathy, and left ventricular dysfunction.
Interstitial Lung Disease, Pneumonia, and Pneumonitis
Among the respiratory, thoracic, and mediastinal disorders reported in the AURA Phase II studies, interstitial lung disease, pneumonitis, respiratory failure and aspiration pneumonia were fatal in 1.5%. The Tagrisso Product Monograph reflects these events, as well as enhanced monitoring for signs of these events, and dose modification instructions to manage ILD-related symptoms. Serious adverse events included a report from the AURAex study of a patient with 'organising pneumonia' which may be related to the unlisted SAE of bronchiolitis obliterans organizing pneumonia (BOOP).
QTc Interval Prolongation
A prolonged QTc interval has been observed in patients treated with Tagrisso. Of the 411 patients in studies AURAex and AURA2, one patient (=1%) had a QTc >500 milliseconds (msec) and 11 patients (2.7%) had an increase from baseline QTc >60 msec. During steady-state treatment, mean changes from baseline in the QTc interval ranged from 13 msec to 16.2 msec over the course of the day. Tagrisso was also associated with a concentration-dependent reduction in heart rate. The Tagrisso Product Monograph includes, in addition to listing QT interval prolongation in the Serious Warnings and Precautions box, a caution when treating patients with cardiac risk factors, and recommends enhanced monitoring to identify signs of QT interval prolongation, and provides dose modification instructions to manage this risk.
Cardiomyopathy and Left Ventricular Dysfunction
The effects of Tagrisso 80 mg daily on ventricular performance were assessed in patients in the AURAex and AURA2 studies. Left ventricular ejection fraction (LVEF) was determined at screening and every 12 weeks relative to the first dose until treatment discontinuation. Statistically significant (p<0.05) mean absolute decreases from baseline in LVEF of 1.0, 1.4, and 1.7 percentage points were observed after echocardiogram/multiple gated acquisition (MUGA) scans at 12, 24, and 36 weeks, respectively. The mean for the worst low change in LVEF at any time during the study was -3.4 (95% CI: -4.07 to -2.78). In these trials, 9/375 (2.4%) of subjects had an LVEF reduction from baseline of ≥10 percentage points to <50%. Fatal congestive heart failure was reported in one patient and Grade 3 ejection fraction decreased in another patient in the AURA Phase II studies. The Tagrisso Product Monograph includes, in addition to listing these events in the Serious Warnings and Precautions box, a cautionary statement regarding patients with cardiac risk factors, enhanced monitoring of patients receiving Tagrisso for relevant cardiac signs/symptoms, and dose modification recommendations.
Other Safety Concerns
The following safety concerns are managed via labelling in the Warning and Precautions section of the Tagrisso Product Monograph. Overall, these risks and other identified toxicities associated with Tagrisso are well-managed via labelling in addition to ongoing safety monitoring.
Ophthalmologic Toxicity
rious ocular disorders, including blindness and endophthalmitis/uveitis were reported in a small number of patients who received Tagrisso and causality could not be ruled out. Keratitis (corneal inflammation) was reported in 2 patients in the AURA Phase II studies, and required dose interruption.
Skin Disorders including Paronychia
The incidence of paronychia was 17.5% in the AURA Phase II studies. Although these were mild to moderate cases, paronychia led to dose reduction in 0.2% of the patients. Due to the insufficient follow-up from the interim data, the incidence of this event is expected to increase with longer exposure. Therefore, the Warnings and Precautions section of the Tagrisso Product Monograph includes paronychia among the skin-related effects in addition to recommendations for prevention measures and relevant treatment.
Embryo-Fetal Toxicity
Based on animal studies, Tagrisso is associated with reproductive and fetal toxicity; therefore, the labelling includes strong warnings to patients to avoid pregnancy.
Hepatobiliary-Related Serious Events
A serious adverse event (SAE) of drug-induced liver injury (a potential Hy's Law case) was reported in a patient from the AURA2 study and in a patient from the compassionate use program, however, due to confounding factors, causality could not be determined. As such, the labelling addresses the risk of hepatotoxicity associated with Tagrisso use.
Safety Conclusion
Patients with EGFR T790M mutation-positive advanced or metastatic NSCLC who progress on EGFR TKI therapy have a serious and life-threatening disease characterized by a low survival rate. Currently there are no market authorized therapies that target the acquired EGFR T790M TKI-resistance-conferring mutation.
Tagrisso, an inhibitor of both EGFR sensitizing mutations (EGFRm) and T790M resistance mutation (T790M), was generally well-tolerated by patients. The most common adverse events were diarrhea, nausea, constipation, stomatitis, skin effects (including rash, dry skin, pruritus, and nail-related events such as paronychia). The more serious, and less common, events have been identified from the submission data. Appropriate warnings and precautions are in place in the approved Tagrisso Product Monograph to address the identified safety concerns.
Overall, the safety profile of Tagrisso is considered acceptable for the target population to be treated. The product 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. In order to ensure that the benefit of Tagrisso therapy continues to outweigh any risk after authorization, Health Canada required several post-approval activities. Further evaluation will take place upon the submission of the requested studies after they become available.
For more information, refer to the Tagrisso Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of Tagrisso for the specified indication.
In vitro studies showed that Tagrisso is a potent and selective irreversible inhibitor of mutant EGFRs. Tagrisso demonstrated anti-tumour activity against NSCLC cell lines and in animal tumour implantation models, both of which harboured EGFR mutations including T790M. Two active metabolites which were present in the plasma at 10% of the parent molecule demonstrated similar inhibition profiles as Tagrisso.
The toxicity profile based on animal studies was generally consistent with the clinical safety profile, especially with regard to decreases in human Ether-à-go-go Related Gene (hERG) current and heart rate, ocular events, gastrointestinal and skin toxicities. Tagrisso also showed embryofetal toxicity, and was transferred via breast milk.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Tagrisso Product Monograph. In view of the intended use of Tagrisso, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Tagrisso 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 Tagrisso 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 is acceptable when the tablets are stored at 15°C to 30°C.
Proposed limits of drug-related impurities are considered adequately qualified; that is, within International Council for Harmonisation 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.
The excipients used in the drug substance and drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TAGRISSO | 02456214 | ASTRAZENECA CANADA INC | OSIMERTINIB (OSIMERTINIB MESYLATE) 40 MG |
| TAGRISSO | 02456222 | ASTRAZENECA CANADA INC | OSIMERTINIB (OSIMERTINIB MESYLATE) 80 MG |