Summary Basis of Decision for Tecentriq

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:

Drug

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Tecentriq is located below.

Recent Activity for Tecentriq

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Tecentriq

Updated: 2025-06-03

The following table describes post-authorization activity for Tecentriq, a product which contains the medicinal ingredient atezolizumab. 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 found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

DIN 02462990 – 1,200 mg/20 mL atezolizumab, solution, intravenous administration (Tecentriq)
DIN 02492393 – 850 mg/14 mL atezolizumab, solution, intravenous administration (Tecentriq)
DIN 02546310 – 125 mg/mL atezolizumab, solution, subcutaneous administration (Tecentriq SC)

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number	Date Submitted	Decision and Date	Summary of Activities
SNDS # 291853	2024-10-31	Issued NOC 2025-01-09	Submission filed as a Level II – Supplement (Safety) to update the PMs for Tecentriq and Tecentriq SC with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.
NC # 289072	2024-07-26	Issued NOL 2024-09-20	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step for Tecentriq SC. The submission was considered acceptable, and an NOL was issued.
Drug product (DIN 02546310) market notification	Not applicable	Date of first sale 2024-05-16	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 273807	2023-03-29	Issued NOC 2024-03-13	Submission filed as a Level I – Supplement for a new subcutaneous route of administration (Tecentriq SC) in the following authorized indications: First-line treatment of extensive-stage small cell lung cancer (ES-SCLC) First-line treatment of non-small cell lung cancer (NSCLC) First-line treatment of hepatocellular carcinoma (HCC) Treatment of locally advanced or metastatic triple-negative breast cancer (TNBC) In addition, the submission was filed for additional dosage regimens of the intravenous formulation of Tecentriq for the authorized TNBC indication. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02546310) was issued for Tecentriq SC. A Regulatory Decision Summary was published.
SNDS # 273336	2023-03-15	Issued NOC 2024-02-19	Submission filed as a Level I – Supplement to update the PM with new efficacy data from the IMbrave 150 study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.
SNDS # 276625	2023-08-11	Issued NOC 2023-12-15	Submission filed as a Level I – Supplement to update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated 2023-06-27, requesting revisions related to the risk of aplastic anemia. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the package insert. An NOC was issued.
NC # 279973	2023-10-13	Issued NOL 2023-12-04	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug product manufacturing facility. The submission was considered acceptable, and an NOL was issued.
Summary Safety Review	Not applicable	Posted 2023-08-17	Summary Safety Review posted for Tecentriq and Keytruda (Assessing the potential risk of aplastic anemia).
NC # 273533	2023-03-21	Issued NOL 2023-07-05	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to reference standard qualification protocol, to the drug product release / shelf-life specifications, and to the approved design space. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 272138	2023-02-03	Issued NOC 2023-06-26	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety data. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
NC # 273033	2023-03-03	Issued NOL 2023-05-02	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug product manufacturing facility. The submission was considered acceptable, and an NOL was issued.
SNDS # 269664	2022-11-14	Issued NOC 2023-04-04	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 262905	2022-03-30	Issued NOC 2023-03-03	Submission filed as a Level I – Supplement submission to expand the dosing regimen to include 840 mg every 2 weeks and 1680 mg every 4 weeks, for the following indications: First-line extensive-stage small cell lung cancer Non-small cell lung cancer First-line unresectable or metastatic hepatocellular carcinoma The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS-C # 247525	2020-12-16	Issued NOC 2022-12-21	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission was filed to remove the conditions for this indication: in combination with nabpaclitaxel, the treatment of adult patients with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD-L1 expression ≥ 1%, and who have not received prior chemotherapy for metastatic disease. Data were provided from studies IMpassion130 and IMpassion131. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2019-09-19 for SNDS # 223911.
New safety and effectiveness review	Not applicable	Started between 2022-09-01 and 2022-09-30	Health Canada started a new safety and effectiveness review for Tecentriq and Keytruda related to aplastic anemia (disease when the body stops producing enough new blood cells).
NC # 264687	2022-05-30	Issued NOL 2022-07-20	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product
SNDS # 261874	2022-02-28	Issued NOC 2022-06-17	Submission filed as a Level II – Supplement (Safety) 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 Warnings and Precautions and Dosage and Administration sections of the PM, and corresponding changes were made to the package insert. An NOC was issued.
SNDS # 254159	2021-06-25	Issued NOC 2022-03-29	Submission filed as a Level I – Supplement to withdraw the indication that had been approved under NDS # 196843, based on the rapidly evolving treatment landscape in prior-platinum (second-line) metastatic urothelial carcinoma. The withdrawn indication was: the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy; or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 254361	2021-06-30	Issued NOC 2022-01-14	Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: as adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adult patients with Stage II to IIIA non-small cell lung cancer (NSCLC) whose tumours have programmed cell death ligand 1 (PD-L1) expression on ≥ 50% of tumour cells (TCs). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 252114	2021-04-26	Issued NOC 2021-12-09	Submission filed as a Level I – Supplement to add drug substance and drug product manufacturing sites, and for a change in scale of the manufacturing process. The information was were reviewed and considered acceptable and an NOC was issued.
SNDS # 245725	2020-10-27	Issued NOC 2021-09-17	Submission filed as a Level I – Supplement to update the PM with pediatric data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
SNDS # 248991	2021-01-29	Issued NOC 2021-06-14	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and to migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
SNDS # 243662	2020-10-26	Issued NOC 2021-03-26	Submission filed as a Level II – Supplement (Safety) to update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated 2020-09-08, requesting revisions related to the risk of autoimmune hemolytic anemia (AIHA). The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the package insert. An NOC was issued.
SNDS-C # 237810	2020-03-30	Issued NOC under NOC/c Guidance 2021-03-05	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c) . The submission was filed to fulfill the commitments made regarding anti-atezolizumab antibodies and neutralizing antibodies. The data were reviewed and considered acceptable, and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c).
SNDS # 237371	2020-03-20	Issued NOC 2021-03-01	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as monotherapy for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have high programmed cell death ligand 1 (PD-L1) expression (PD-L1 stained ≥ 50% of tumour cells [TCs] or PD-L1 stained tumour-infiltrating immune cells [ICs] covering ≥ 10% of the tumour area), as determined by a validated test and who do not have epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Summary Safety Review	Not applicable	Posted 2021-02-03	Summary Safety Review posted for Tecentriq (Assessing the potential risk of autoimmune hemolytic anemia).
SNDS # 243333	2020-08-27	Issued NOC 2021-01-13	Submission filed as a Level II – Supplement (Safety) to update the PM with safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.
NC # 243485	2020-08-31	Issued NOL 2020-12-17	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 242702	2020-08-12	Cancellation Letter Received 2020-08-24	Submission filed as a Level II – Supplement (Safety) to update the PM with safety information and to change in the labelled storage conditions for the drug product. The proposed revisions exceeded the scope of a Level II Supplement as it also contained quality-related changes. The submission was therefore cancelled administratively by the sponsor.
SNDS # 235450	2020-01-24	Issued NOC 2020-08-10	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with bevacizumab, the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma who require systemic therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS-C # 217798	2018-06-28	Issued NOC under NOC/c Guidance 2020-05-20	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c), to address commitments 2a and 2b in the Letter of Undertaking for NDS # 196843. The submission provided analyses for the studies IMvigor211 and IMvigor210 and updated the PM with the information. The information was reviewed; commitment 2a was modified and 2b was considered to be fulfilled. An NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c).
SNDS # 226905	2019-04-16	Issued NOC 2020-04-02	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with carboplatin and nabpaclitaxel, the first-line treatment of adult patients with metastatic non-squamous non-small cell lung cancer (NSCLC) who do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
New safety and effectiveness review	Not applicable	Started between 2020-01-01 and 2020-01-31	Health Canada started a new safety and effectiveness review for Tecentriq related to autoimmune hemolytic anemia (disease when the body’s immune system attacks and destroys its own red blood cells).
SNDS # 224569	2019-02-11	Issued NOC 2020-01-21	Submission filed as a Level I - Supplement to seek approval of two additional dosing regimens (840 mg Q2W and 1680 mg Q4W) of atezolizumab as alternatives to the authorised 1200 mg Q3W regimen for the second-line non-small lung cancer (2L NSCLC) indication only. Based on the results from pharmacokinetic modelling and simulation, exposure-response assessments, safety analyses, and immunogenicity data, the risk-benefit profile of the proposed dose regimens of 840 mg Q2W and 1680 mg Q4W atezolizumab in the authorised 2L NSCLC indication is considered to be favourable. An NOC was issued.
NC # 233061	2019-10-31	Issued NOL 2019-12-27	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, Adverse Reactions, and Dosage and Administration sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 229608	2019-07-11	Issued NOL 2019-10-16	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change testing procedures for the drug substance, and to transfer a quality control test to a new facility. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02492393) market notification	Not applicable	Date of first sale 2019-10-16	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
PBRER-C # 224004	2019-01-24	Cleared 2019-10-07	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-05-18 to 2018-11-17. The information was reviewed and found acceptable
SNDS # 223911	2019-01-21	Issued NOC under NOC/c Guidance 2019-09-19	Submission filed as a Level I – Supplement to for a new indication and a new vial presentation. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: in combination with nabpaclitaxel, the treatment of adult patients with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD-L1 expression ≥ 1%, and who have not received prior chemotherapy for metastatic disease. The submission was reviewed and considered acceptable, and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c). A new DIN (02492393) was issued for the new presentation. A Regulatory Decision Summary was published.
SNDS # 223753	2019-01-16	Issued NOC 2019-08-08	Submission filed as a Level I - Supplement to add a new indication for Tecentriq. The indication authorized was Tecentriq (atezolizumab), in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). Regulatory Decision Summary published.
SNDS # 217324	2018-06-15	Issued NOC 2019-05-24	Submission filed as a Level I - Supplement to add a new indication for Tecentriq. The indication authorized was Tecentriq in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of adult patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumour aberrations, and no prior systemic chemotherapy treatment for metastatic non-squamous NSCLC. Regulatory Decision Summary published.
Dear Healthcare Professional Letter	Not applicable	Posted 2019-03-13	Dear Healthcare Professional Letter posted, containing important safety information for healthcare professionals.
PBRER-C # 218630	2018-07-25	Cleared 2019-01-25	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-11-18 to 2018-05-17. The information was reviewed and found acceptable
NC # 220475	2018-09-26	Issued NOL 2018-12-17	Submission filed as a Level II (90 day) Notifiable Change to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 216418	2018-05-17	Issued NOC 2018-11-26	Submission filed as a Level I - Supplement for a new drug product manufacturing site. The information was reviewed and considered acceptable. An NOC was issued.
PBRER-C # 213070	2018-01-24	Cleared 2018-08-23	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-05-18 to 2017-11-17. The information was reviewed and found acceptable
SNDS # 205038	2017-04-26	Issued NOC 2018-04-06	Submission filed as a Level I - Supplement for new indication: Tecentriq (atezolizumab) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have disease progression on a therapy for these aberrations prior to receiving Tecentriq. Regulatory Decision Summary published.
Dear Healthcare Professional Letter	Not applicable	Posted 2018-02-14	Dear Healthcare Professional Letter posted, containing important safety information for healthcare professionals and hospitals.
NC # 209378	2017-09-14	Issued NOL 2017-12-13	Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions, Dosage and Administration, and Clinical Trials sections of the PM. Corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 207899	2017-07-26	Cleared 2017-08-29	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-11-18 to 2017-05-17. The information was reviewed and found acceptable.
NC # 205692	2017-05-17	Issued NOL 2017-07-11	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02462990) market notification	Not applicable	Date of first sale: 2017-05-02	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 196843	2016-07-18	Issued NOC under NOC/c Guidance 2017-04-12	Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.

Summary Basis of Decision (SBD) for Tecentriq

Date SBD issued: 2017-05-30

The following information relates to the New Drug Submission for Tecentriq.

Atezolizumab
1200 mg/vial, solution, intravenous

Drug Identification Number (DIN):

02462990

Hoffmann-La Roche Ltd.

New Drug Submission Control Number: 196843

On April 12, 2017, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Hoffmann-La Roche Limited for the drug product, Tecentriq. 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 Tecentriq is favourable for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

Have disease progression during or following platinum-containing chemotherapy
Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

1 What was approved?

Tecentriq, an antineoplastic agent, was authorized for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

Have disease progression during or following platinum-containing chemotherapy
Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

Marketing authorization with conditions was based on tumour response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established.

No overall differences in safety or efficacy were observed between patients ≥65 years of age and younger patients.

The safety and efficacy of Tecentriq in children and adolescents below 18 years of age have not been established.

Tecentriq is contraindicated for patients with a known hypersensitivity to atezolizumab or any of the excipients. Tecentriq was approved for use under the conditions stated in the Tecentriq Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Tecentriq (atezolizumab, 1200 mg/vial) is presented as concentrate for solution for intravenous infusion. In addition to the medicinal ingredient, the solution contains glacial acetic acid, L-histidine, polysorbate 20, sucrose, and water for injection.

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 Tecentriq Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Tecentriq approved?

Health Canada considers that the benefit/risk profile of Tecentriq is favourable for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

Have disease progression during or following platinum-containing chemotherapy
Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

Tecentriq 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.

In Canada, urothelial carcinoma (UC) is the fourth most common cancer among men and the eleventh most common cancer among women. Patients diagnosed with locally advanced or metastatic UC have poor prognoses with only 5.5% surviving at least 5 years. There are no authorized agents available to patients that have locally advanced or metastatic UC who have failed first-line platinum based chemotherapy. New treatment options are needed for patients with this life-threatening disease.

The activity of Tecentriq has been investigated in patients with various types of tumours. This market authorization with conditions was based primarily on a Phase II, multicentre, international, single-arm clinical study that enrolled 310 patients with locally advanced or metastatic urothelial carcinoma who had progression of disease during or after platinum-containing chemotherapy in the metastatic setting or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. In these 310 patients, the objective response rate (ORR) was 14.8% (95% confidence interval [CI]: 11.1, 19.3) and the complete response (CR) rate was 5.5%. The duration of response was not estimable; 82% of responders maintained their response for at least 1 year. These results suggest that Tecentriq is associated with a modest objective response rate, but with deep and durable responses in this heavily pre-treated, difficult to treat population.

The safety profile of Tecentriq was well characterized and is consistent with other authorized monoclonal antibody checkpoint inhibitors that target the PD-1/PD-L1 signaling pathway. Adverse reactions associated with the use of Tecentriq are generally manageable with close monitoring and prompt intervention. Given the lack of therapeutic options available to patients within the indication, the evidence provided in support of the efficacy of Tecentriq is considered promising such that the tentative benefit-risk balance can be considered favourable. Confirmation of efficacy in a well-controlled, randomized clinical study is necessary to confirm a positive benefit/risk balance for Tecentriq and is a condition of market authorization. Other post-market conditions are stated in response to question 4 What follow-up measures will the company take?

A Risk Management Plan (RMP) for Tecentriq was submitted by Hoffmann-La Roche Limited to Health Canada. Upon review, Health Canada proposed that immune-mediated skin reactions be added to the RMP in order for it to be acceptable. In return, the sponsor adequately addressed the concern. 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 Tecentriq has been deemed acceptable.

Overall, the promising evidence of efficacy is considered to outweigh the potential risks of Tecentriq. The safety profile of Tecentriq has been well-characterized in non-clinical and clinical studies and is considered manageable with close monitoring and prompt intervention, where necessary. Appropriate warnings and precautions are in place in the Tecentriq Product Monograph to address the identified safety concerns and to provide guidance on the management of potential adverse reactions. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Tecentriq will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

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 Tecentriq?

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 Tecentriq. 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: Tecentriq

Submission Milestone	Date
Pre-submission meeting:	2016-05-11
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance:	2016-07-13
Submission filed:	2016-07-18
Screening
Screening Acceptance Letter issued:	2016-08-19
Review
On-Site Evaluation:	2017-01-23 - 2017-01-27
On-Site Evaluation:	2017-01-30 - 2017-02-03
Quality Evaluation complete:	2017-03-01
Labelling Review complete:	2017-02-28
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued:	2017-03-07
Review of Response to NOC/c-QN:
Response filed (Letter of Undertaking):	2017-03-10
Clinical Evaluation complete:	2017-03-28
Labelling Review complete:	2017-04-04
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate/Biologics and Genetic Therapies Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance:	2017-04-12

The Canadian regulatory decision on the non-clinical and clinical review of Tecentriq was based on a critical assessment of the Canadian data package.

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 additional following reports:

The final report for the confirmatory study, IMvigor211: A Phase III, open-label, multicentre, randomized study to investigate the efficacy and safety of Tecentriq (atezolizumab) compared with chemotherapy in patients with locally advanced or metastatic urothelial carcinoma after failure with platinum containing chemotherapy. This study is designed to evaluate the effect of atezolizumab on overall survival (OS) when compared to chemotherapy (investigator's choice of docetaxel, paclitaxel or vinflunine).
1. The sponsor acknowledges that the indication for Tecentriq can be withdrawn if this study does not demonstrate an improvement in overall survival (OS) and in the overall benefit-risk profile compared to chemotherapy.
2. The sponsor commits to explore treatment outcomes by PD-L1 expression. The predictive value of PD-L1 expression on both tumour infiltrating immune cells and tumour cells will be explored.
Mature estimates of the secondary analyses (i.e., duration of response) of the pivotal study, IMvigor210 (Cohort 2).
The final clinical study report of a clinical study to evaluate the effect of Tecentriq on thyroid function tests and clinical thyroid disease.
An assay with improved sensitivity for the detection of neutralising antibodies against atezolizumab in the presence of atezolizumab levels that are expected to be present in samples at the time of patient sampling.
The final study report for the study, Investigation of the Immune Response to Keyhole Limpet Hemocyanin (KLH) Challenge in Male and Female Cynomolgus Monkeys Following Administration of Atezolizumab.

5 What post-authorization activity has taken place for Tecentriq?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Tecentriq is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

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.
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

Atezolizumab, the medicinal ingredient in Tecentriq, is an Fc-engineered humanized immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 protein and blocks interactions with the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 pathway-mediated inhibition of the immune response, resulting in reactivation of the anti-tumour immune response.

The clinical pharmacology was characterized in one study in patients with urothelial carcinoma. The study was a Phase I dose-escalation study of the safety and pharmacokinetics (PK) of atezolizumab administered via intravenous infusion. The study also enrolled patients with various tumour types including ovarian, gastric, colorectal, head and neck, melanoma, triple-negative breast cancer, clear cell renal cell cancer, and non-small cell lung cancer. Based on these data, two population PK reports were generated to further characterize the clinical pharmacology of atezolizumab in urothelial carcinoma patients.

The reported PK parameters were generated based on the data from all patients enrolled as of the clinical data cut-off. The non-compartmental analysis of serum concentrations from 473 PK-evaluable patients, across a variety of tumour types, suggested that atezolizumab PK is linear in the dose range of 1-20 mg/kg. The observed increases in systemic exposure were dose-proportional and there were no significant changes in clearance or elimination half-life with increasing dose.

Population PK analyses based on 423/429 (98.6%) urothelial carcinoma patients enrolled in the pivotal efficacy study IMvigor210, and treated with 1,200 mg atezolizumab every 3 weeks, suggested that none of gender, body weight, serum albumin, tumour burden, nor the presence of anti-therapeutic antibodies, affected individual PK parameters in a clinically meaningful way.

Exposure-response analyses indicated that steady-state exposure of atezolizumab administered as 1,200 mg every 3 weeks is not a significant predictor of either the probability of response or the probability of suffering an adverse event.

Overall, the clinical pharmacology of Tecentriq has been sufficiently characterized in patients with locally advanced or metastatic urothelial carcinoma.

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

Clinical Efficacy

The clinical efficacy of Tecentriq (atezolizumab) was evaluated in one Phase II, single-arm, multicentre, international study (IMvigor210) that enrolled patients with locally advanced or metastatic urothelial carcinoma. All patients were prospectively evaluated for PD-L1expression on both tumour cells and immune cells using a validated immunohistochemistry assay (Ventana SP142). The study was composed of two cohorts where patients were enrolled based on prior treatment status. Cohort 1 patients were treatment-naïve for advanced urothelial carcinoma and considered cisplatin ineligible (number of patients [n] = 119). Cohort 2 patients received at least 1 prior platinum-based treatment regimen in the neo-adjuvant, adjuvant or metastatic setting (n = 310). Of the 310 patients treated with Tecentriq in Cohort 2, 210 patients had <5% immune cell PD-L1 expression and 100 patients had immune cell PD-L1 expression ≥5%. The majority of patients in Cohort 2 had received two or more prior systemic chemotherapy regimens (61.9%). All patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Cohort 2 was considered pivotal for this drug submission as it represented the population targeted with the proposed indication.

The sponsor pre-defined a sequential testing design based on PD-L1 expression level to maintain the type-I error at 5%. The independent review facility (IRF) used Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria and the investigator used modified RECIST immune response criteria to determine the overall response rates against a historically-derived response rate of 10%. However, the historically-derived response rate of 10% was questioned given that it was based on a systematic review of responses observed in a true second-line metastatic urothelial carcinoma population, whereas the population enrolled in the IMvigor210 study was more heavily pre-treated. Also, although a focus was maintained on randomized studies, the response rates were derived from studies of a wide variety of single-agent regimens to which the rates of response were highly variable. However, it was recognised that salvage therapies are often not used in this setting, and that treatment options are limited. Therefore, the response results were considered in light of the fact that there are few options for the majority of patients at this stage of their disease.

Based on the most up-to-date results (November 27, 2015), the IRF assessment confirmed the overall response rate as per RECIST version 1.1 to be 14.8% (95% confidence interval [CI]: 11.1, 19.3) for the all-comers (number [n] = 310) population. The complete response rate in the all-comers population was 5.5%. In patients with PD-L1 immune cell expression <5% (n = 210), the confirmed overall response rate was lower than observed overall (9.5% [95% CI: 5.9, 14.3]); however, low PD-L1 expression was not sufficient to exclude the possibility of response or complete response (CR = 5 [2.4%]). Patients with immune cell PD-L1 expression ≥5% (n = 100) had a confirmed overall response rate of 26.0% (95% CI: 17.7, 35.7) and a complete response rate of 12.0% suggesting that the probability of response increases with higher immune cell PD-L1 expression. However, the predictive value of immune cell PD-L1 expression in urothelial carcinoma needs further exploration in the setting of a randomised, well-controlled clinical study.

Duration of response was not estimable (NE) (95% CI: 12.7, NE) for the all-comers population with 81.7% of responders still in response at 1 year. For the <5% immune cell PD-L1 group of patients, the median duration of response was 12.7 months (95% CI: NE). For the ≥5% immune cell PD-L1 group, the median duration of response was NE (95% CI: NE). At the 12-month landmark analysis, 84.6% of responding immune cell PD-L1 ≥5% patients had not progressed.

In summary, Tecentriq was associated with a modest overall response rate in a heavily pre-treated, difficult to treat population. The observed responses were durable compared to previously reported responses obtained with salvage chemotherapy. Given the lack of therapeutic options available for this set of patients, the evidence provided in support of the efficacy of Tecentriq is considered promising. Confirmation of efficacy in a well-controlled, randomized clinical study is necessary to confirm the benefit/risk balance for Tecentriq and is a condition of authorization. Tecentriq has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. See question 4 What follow-up measures will the company take? Patients should be advised of the nature of the authorization.

Indication

The New Drug Submission for Tecentriq was filed with the following indication.

Tecentriq (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma after prior chemotherapy.

Health Canada recommended that the sponsor revise the indication to adequately reflect the characteristics of the patients enrolled in the pivotal study for this submission. Health Canada authorized the following indication:

Tecentriq (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
- Have disease progression during or following platinum-containing chemotherapy
- Have disease progression within 12 months of neo-adjuvant or adjuvant treatment with platinum-containing chemotherapy

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

Clinical Safety

The clinical safety of Tecentriq (atezolizumab) was primarily based on use in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following prior platinum-based chemotherapy or who had disease progression within 12 months of platinum-based neoadjuvant or adjuvant chemotherapy. These patients were enrolled in Cohort 2 of the Phase II single-arm multicentre, international clinical study, IMvigor210, in which patients received Tecentriq 1,200 mg every 3 weeks by intravenous infusion until there was no longer a clinical benefit as assessed by investigators or until unacceptable toxicity. The Cohort 2 population was pivotal for this drug submission as it represented the population targeted with the proposed indication. Cohort 1 patients were treatment naïve and considered cisplatin ineligible (n = 119). Cohort 1 was reviewed, along with the results of Cohort 2 and a Phase I dose-escalation study (n = 92 patients with metastatic urothelial carcinoma) in the evaluation of safety. Additional safety information was available based on studies carried out across a variety of tumour types, but predominantly in patients with non-small cell lung cancer (NSCLC, n = 1,026).

Overall, 303/310 (97.7%) patients enrolled in Cohort 2 had at least one adverse event and grade 3-4 events were experienced by 186 (60.0%) patients. Serious adverse events occurred in 144 (46.5%) patients. Adverse events leading to death occurred in 3 (1.0%) patients. Adverse events leading to dose interruption occurred in 100 (32.3%) patients and withdrawal from Tecentriq due to adverse events occurred in 12 (3.9%) patients.

In Cohort 2, the most common adverse events (reported by ≥10% patients) were fatigue (51.0%), decreased appetite (27.1%), nausea (26.5%), constipation (26.1%), urinary tract infection (23.2%), pyrexia (22.3%), peripheral edema (14.2%), diarrhea (21.6%), vomiting (19.4%), back pain (18.1%), dyspnea (17.4%), chills (10.6%), arthralgia (17.7%), anemia (17.1%), cough (16.5%), hematuria (16.1%), pruritus (14.8%), abdominal pain (13.9%), rash (11.6%), pain in extremities (10.3%), headache (10.0%), and pain (10.0%). The majority of adverse reactions were mild to moderate (Grade 1 or 2) in severity. The most common adverse events leading to dose interruption were urinary tract infection (2.6%), diarrhea, pyrexia (2.3% each), fatigue (1.9%), increased blood bilirubin, dyspnea and pneumonitis (1.6% each), increased aspartate aminotransferase, increased blood creatinine, confusional state, hypotension, sepsis and increased transaminases (1.3% each). Two patients were withdrawn from Tecentriq due to sepsis.

Immune-related adverse events (AEs) are well known to occur in patients receiving checkpoint inhibitors, including atezolizumab. Immune-related adverse events were identified through ongoing analysis of IMvigor210 Cohort 2 as well as other studies across a variety of tumour types in which atezolizumab had been tested. Identified immune-related AEs included pneumonitis, colitis, hepatitis, endocrinopathies (hypophysitis, diabetes mellitus, hyperthyroidism, hypothyroidism), and others (uveitis and skin reactions). In clinical studies, most immune-related AEs were reversible and managed with dose interruption, administration of corticosteroids and/or supportive care. Immune-related adverse events are adequately described in the Tecentriq Product Monograph and measures for the management of immune related AEs have been included in the Warnings and Precautions and the Dosage and Administrations sections.

Post-marketing safety data is not available for Tecentriq.

Appropriate warnings and precautions are in place in the approved Tecentriq Product Monograph to address the identified safety concerns.

For more information, refer to the Tecentriq 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 atezolizumab, the medicinal ingredient of Tecentriq, for the specified indication.

Atezolizumab binds with comparable affinity to human, mouse and monkey PD-L1, and prevented the interaction between PD-L1 and its receptors PD-1 and B7-1. Treatment with anti-PD-L1 during chronic infection (Day 14) in a mouse model of lymphocytic choriomeningitis virus (LCMV) reduced viral titres and enhanced cytotoxic T cell function consistent with an immune-modulatory mode of action. However, anti-PD-L1 treatment at the time of peak LCMV infection (Day 7) resulted in substantially reduced survival indicating the potential of atezolizumab to worsen the severity of some infections, particularly in the setting of high viral burden. Atezolizumab reduced tumour growth in several syngeneic murine tumour models providing proof-of-concept evidence in support of its anti-tumour activity.

Three repeat-dose toxicology studies were conducted including a 2-week study in mice, and 8- and 26-week studies in cynomolgus monkeys. No unscheduled mortalities occurred. Atezolizumab-related findings included sciatic neuropathy and arteritis/periarteritis. Both findings are consistent with increased autoimmune reactivity. Unexpectedly, atezolizumab treatment resulted in reversible irregular menstrual cycling in all females at the 50 mg/kg dose correlating with the absence of fresh corpora lutea, suggesting an adverse effect on fertility during treatment. The 50 mg/kg dose results in approximately 6 times the exposure compared to the recommended clinical dose.

No atezolizumab-specific developmental or reproductive studies were conducted. Previous studies have shown that inhibition of PD-L1/PD-1 signalling results in adverse pregnancy outcomes including abortion. Appropriate warnings and precautionary measures are in place in the Tecentriq Product Monograph to address the identified safety concerns.

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

7.3 Quality Basis for Decision

Atezolizumab, the medicinal ingredient of Tecentriq, is a humanized immunoglobulin G1 (IgG1) monoclonal antibody. Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid substitution which results in a non-glycosylated antibody that has minimal binding to Fc receptors. Atezolizumab targets human PD-L1 on tumour-infiltrating immune cells and tumour cells and inhibits its interaction with its receptors, PD-1 and B7.1.

Tecentriq (atezolizumab) is supplied as a single-use vial containing 20 mL of preservative-free, colourless to slightly yellow solution, at a concentration of 60 mg/mL for dilution for intravenous infusion. Each vial of Tecentriq contains a total of 1,200 mg atezolizumab. Non-medicinal ingredients include glacial acetic acid, L-histidine, polysorbate 20, sucrose, and water for injection.

Characterization of the Drug Substance

Extensive characterization of the physicochemical, biological, and immunological properties of atezolizumab and confirmation of its purity were performed using methods selected in accordance with International Council for Harmonisation (ICH) guidelines (ICH Q6B). These studies and the formal validations studies demonstrated that the drug substance manufacturing facility is able to consistently manufacture atezolizumab of acceptable quality.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The drug substance, atezolizumab, is manufactured using Chinese hamster ovary (CHO) cells. The cell culture manufacturing process consists of three stages: seed train, inoculum train, and production culture. Upon completion of the production culture, atezolizumab in the cell culture fluid is physically separated from the CHO cells by harvesting via centrifugation and filtration. After harvesting, atezolizumab is purified by Protein A affinity column chromatography, low-pH viral inactivation, cation-exchange column chromatography, multimodal anion-exchange column chromatography, and small-virus retentive filtration steps. The drug substance is finally formulated via ultrafiltration and diafiltration.

The drug product manufacturing process consists of thawing and mixing of the formulated drug substance, sterile filtration, filling and capping followed by visual inspection, and container closure integrity testing. The sponsor has demonstrated the ability of the drug product manufacturing site to consistently produce drug product of acceptable quality.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at 2°C to 8°C for Tecentriq is considered acceptable when the product is protected from light and freezing.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

On-Site Evaluations of the facilities involved in the manufacture and testing of the drug substance, atezolizumab, and the drug product, Tecentriq, have been successfully conducted by Health Canada.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

Related Drug Products

Product name	DIN	Company name	Active ingredient(s) & strength
TECENTRIQ	02462990	HOFFMANN-LA ROCHE LIMITED	ATEZOLIZUMAB 1200 MG / 20 ML

Date modified:: 2026-04-19

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