Summary Basis of Decision for Bavencio

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

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

Recent Activity for Bavencio

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 Bavencio

Updated: 2024-02-06

The following table describes post-authorization activity for Bavencio, a product which contains the medicinal ingredient avelumab. 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 02469723 - 20 mg/mL, avelumab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

PBRER-C # 264758

2022-05-31

Filed 2022-08-19

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2021-03-23 to 2022-03-22. The information was reviewed and found acceptable.

SNDS # 257273

2021-10-12

Issued NOC 2022-08-15

Submission filed as a Level I – Supplement to update the PM with results from Study MS100070-0306, a Phase I study evaluating avelumab in pediatric patients with relapsed or refractory solid tumours. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Pharmacology section of the PM and an NOC was issued.

NC # 259235

2021-12-01

Issued NOL 2022-03-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 253262

2021-05-31

Filed 2021-09-10

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2020-03-23 to 2021-03-22. The information was reviewed and found acceptable.

NC # 250917

2021-03-18

Issued NOL 2021-06-21

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance and drug product release or shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 241006

2020-06-24

Cleared 2021-04-12

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2019-09-23 to 2020-03-22. The information was reviewed and found acceptable.

NC # 247747

2020-12-18

Issued NOL 2021-02-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS-C # 235471

2020-02-05

Issued NOC 2021-01-13

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) for the treatment of metastatic Merkel cell carcinoma (MCC). This submission provides confirmatory evidence to support the metastatic MCC indication as per the Letter of Undertaking dated October 29, 2019 for SNDS #225974 and November 20, 2017 for NDS #204052. The sponsor provided data from confirmatory Study EMR100070-003 Part B. The submission was reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOCs that had been issued November 20, 2017, and October 29, 2019.

SNDS # 240024

2020-05-27

Issued NOC 2020-12-10

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: Bavencio is indicated for the maintenance treatment of patients with unresectable locally advanced or metastatic urothelial carcinoma whose disease has not progressed following first-line platinum-based chemotherapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

PBRER-C # 234046

2019-11-28

Filed 2020-07-13

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2019-03-23 to 2019-09-22. The information was reviewed and found acceptable.

SNDS # 226954

2019-04-18

Cancellation Letter Received 2020-06-30

Submission filed as a Level I – Supplement to seek authorization for the marketing of Bavencio (avelumab), in combination with axitinib, as first-line treatment for patients with advanced Renal Cell Carcinoma. A Notice of Non-compliance was issued by Health Canada on April 02, 2020. Health Canada had identified some deficiencies in the data and the sponsor chose to cancel their submission in order to re-file at a later date with additional data. A Summary of Cancellation was published.

NC # 236352

2020-02-21

Issued NOL 2020-04-24

Submission filed as a Level II (90 day) Notifiable Change to update the PM to include myasthenia gravis/myasthenic syndrome as an adverse reaction related to the use of Bavencio. 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 NOL was issued.

NC # 235112

2020-01-14

Issued NOL 2020-04-16

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance and drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 228207

2019-05-30

Cleared

2019-12-12

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-09-23 to 2019-03-22. The information was reviewed and found acceptable.

SNDS # 225974

2019-03-21

 

Issued NOC under NOC/c Guidance

2019-11-06

Submission filed as a Level I - Supplement for a new indication for Bavencio. The indication authorized was for the treatment of adult patients with metastatic Merkel cell carcinoma. Regulatory Decision Summary published.

NC # 232003

2019-09-27

Issued NOL

2019-10-29

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 222509

2018-11-29

Cleared

2019-05-31

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-03-23 to 2018-09-22. The information was reviewed and found acceptable.

NC # 224491

2019-02-07

Issued NOL

2019-05-17

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 of the PM, and 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-C # 217596

2018-06-26

Issued NOC under NOC/c Guidance

2019-05-14

Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission contained estimates of efficacy endpoints based on at least 12 months of follow-up. This report also provided mature estimates of the duration of response. The NOC/c authorization was based on this same population for the 161 subjects who had at least 6 months of follow-up at the interim analysis. Overall, the results from this 12-month clinical study report were consistent with those observed at the time of the NOC/c issuance. The review of this submission fulfills commitment “b” listed in the Letter of Undertaking (dated 2018-04-10). An NOC under the NOC/c Guidance was issued.

PBRER-C # 216804

2018-05-31

Cleared

2018-10-17

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-09-23 to 2018-03-22. The information was reviewed and found acceptable.

NDS # 208742

2017-08-24

Issued NOC under NOC/c Guidance 2018-05-04

Submission filed for conditional market authorization for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received prior platinum-based chemotherapy. Regulatory Decision Summary published.

Drug product (DIN 02469723) market notification

Not applicable

Date of first sale: 2017-12-18

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 204052

2017-03-23

Issued NOC under NOC/c Guidance 2017-12-08

Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.

 
Summary Basis of Decision (SBD) for Bavencio

Date SBD issued: 2018-03-09

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

Avelumab
20 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02469723

EMD Serono

New Drug Submission Control Number: 204052

 

On December 18, 2017, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to EMD Serono, a Division of EMD Inc., Canada, for the drug product Bavencio. 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 effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Bavencio is favourable for the treatment of metastatic Merkel cell carcinoma in previously treated adults. Marketing authorization with conditions was based on tumour response and durability of response. An improvement in survival or disease-related symptoms has not yet been established.

 

1 What was approved?

 

Bavencio, an antineoplastic, was authorized for the treatment of metastatic Merkel cell carcinoma in previously treated adults. Bavencio is a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1). It binds PD-L1 and blocks the interaction between PD-L1 and its receptors, programmed death 1 (PD-1) and B7.1. This removes the suppressive effects of PD-L1 on antitumour CD8+ T cells, and results in the restoration of antitumour T-cell responses.

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

Bavencio is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Overall differences in safety or efficacy between elderly patients (65 years of age and over) and younger patients (under 65 years of age) have not been evaluated.

The safety and efficacy of Bavencio in pediatric patients (under 18 years of age) have not been established.

Bavencio was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Bavencio (20 mg/mL avelumab) is presented as a solution for intravenous infusion. In addition to the medicinal ingredient, the solution contains D-mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, 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 Bavencio Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Bavencio approved?

 

Health Canada considers that the benefit-risk profile of Bavencio is favourable for the treatment of metastatic Merkel cell carcinoma in previously treated adults. Bavencio 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.

Merkel cell carcinoma is a rare and aggressive neuroendocrine tumour of the skin. Metastatic Merkel cell carcinoma is a serious and life-threatening disease with poor prognosis and survival. In Canada, there are no approved treatment options, nor are there any therapies that demonstrate durable response and survival benefit for metastatic Merkel cell carcinoma.

Bavencio, an immune checkpoint inhibitor, is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that binds programmed death ligand 1 (PD-L1) and blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1. This removes the suppressive effects of PD-L1 on antitumour CD8+ T cells, and results in the restoration of the cytotoxic T-cell response.

The efficacy and safety of Bavencio were evaluated in Part A of an ongoing pivotal Phase II, open-label, single-arm, multicentre study, known as Study EMR100070-003 (Study 003 Part A). It involved 88 patients with histologically confirmed metastatic Merkel cell carcinoma whose disease had progressed after at least one chemotherapy treatment for distant metastatic disease. Best overall response, the primary efficacy endpoint of the study, was confirmed in 29 patients (33%, 95% confidence interval [CI]: 23.3%, 43.8%), consisting of 10 complete responses (11.4%) and 19 partial responses (21.6%). Clinically relevant durable response (6 months or longer) was achieved in 25/88 patients (28.4%). At 12 months after the start of treatment, the response was maintained in 21 patients (23.9%).

The safety of Bavencio at the recommended dose of 10 mg/kg intravenously every two weeks was evaluated in a total of 1,738 patients, including 1,650 patients with other solid tumours from Study EMR100070-001 (Study 001) and 88 patients with metastatic Merkel cell carcinoma from Study 003 Part A. At the time of data cut-off, the median duration of treatment was 12 weeks in Study 001 and 17 weeks in Study 003 Part A.

The risks associated with Bavencio are primarily due to its mechanism of action, i.e., blocking of the PD-1/PD-L1 pathway. The two primary safety concerns are immune-mediated adverse drug reactions and infusion reactions. Immune-mediated adverse drug reactions associated with Bavencio treatment included pneumonitis, myocarditis, endocrinopathies (thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus), hepatitis, colitis, nephritis, myositis and skin reactions. The frequency, severity, duration and types of immune-mediated adverse drug reactions associated with Bavencio were, in general, consistent with those reported for other PD-1/PD-L1 inhibitors. Infusion reactions occurred in 21.6% and 25.5% of patients, and ≥Grade 3 infusion reactions were reported in 0% and 0.7% of patients in Study 003 Part A and Study 001, respectively.

The infusion reactions were manageable with temporary interruptions, infusion rate reductions and administration of symptomatic treatment including antihistamines and corticosteroids. Appropriate patient premedication (with an antihistamine and acetaminophen) is required prior to the first four infusions of Bavencio, as highlighted in the Bavencio Product Monograph. The most common adverse events as well as serious adverse events were consistent with those reported in similar patient populations.

The risks associated with Bavencio therapy, including immune-mediated adverse drug reactions and infusion reactions, have been appropriately addressed in the Warnings and Precautions section of the Bavencio Product Monograph.

Based on its mechanism of action and data from published animal studies, Bavencio can cause fetal harm. This safety concern has also been included in the Warnings and Precautions section of the Bavencio Product Monograph.

A Risk Management Plan (RMP) for Bavencio was submitted by EMD Serono, a Division of EMD Inc., Canada, to Health Canada. During the review, immune-mediated renal dysfunction, new-onset type 1 diabetes mellitus, and skin reactions were recategorized from potential risks to important identified risks of Bavencio. The revised 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 Bavencio was accepted.

Overall, Bavencio has demonstrated a clinically relevant durable response in patients with metastatic Merkel cell carcinoma who have received one or more lines of systemic therapy. The safety profile of Bavencio is acceptable and consistent with that of other immune checkpoint inhibitors. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Bavencio Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance monitoring the safety of Bavencio will be ongoing. Further evaluation will take place upon the submission of the final report of the ongoing confirmatory trial (Study EMR100070-003 Part B).

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 Bavencio?

 

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 for Bavencio. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness in patients with metastatic Merkel cell carcinoma, a population of patients with an unmet medical need. Subsequent review led to the decision to issue the sponsor market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

 

Submission Milestones: Bavencio

Submission Milestone Date
Pre-submission meeting: 2016-12-02
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: 2017-01-25
Submission filed: 2017-03-23
Screening  
Screening Acceptance Letter issued: 2017-04-21
Review  
On-Site Evaluation: 2017-09-19 - 2017-09-22
Quality Evaluation complete: 2017-11-06
Clinical Evaluation complete: 2017-11-07
Review of Risk Management Plan complete: 2017-08-28
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-11-03
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: 2017-11-07
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking): 2017-11-20
Clinical Evaluation complete: 2017-11-30
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2017-12-18

 

The Canadian regulatory decision on the non-clinical and clinical review of Bavencio was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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's commitments include (but are not limited to) submitting to Health Canada:

  • A Supplemental New Drug Submission-Confirmatory (SNDS-c), which will include the following:
    • The final study report for the confirmatory trial, Study EMR100070-003 Part B entitled "A single-arm, multicentre study to investigate efficacy and safety of avelumab in previously untreated adults with metastatic Merkel cell carcinoma", with a primary analysis conducted at a minimum of 15 months after the last patient has received treatment (the report should be submitted no later than January 30, 2020).
    • A validated assay for avelumab neutralizing antibody testing.
  • Status reports on the progress of the ongoing confirmatory trial, on an annual basis and within 60 calendar days of the market authorization anniversary. Submission of annual status reports will terminate upon filing of the confirmatory trial final report.

The sponsor has acknowledged that the current indication for Bavencio could be withdrawn if the final report of Study EMR100070-003 Part B fails to demonstrate that the overall risk-benefit assessment is favourable, as determined by Health Canada.

The sponsor has also agreed to provide Health Canada with post-market safety monitoring information, including (but not limited to):

  • Reports of all serious adverse drug reactions for Bavencio that occur in Canada and all serious unexpected adverse drug reactions for Bavencio that occur outside of Canada, within 15 days of their occurrence, in accordance with current regulations. Reports of adverse events and adverse drug reactions occurring in the confirmatory Study EMR100070-003 Part B will also be submitted to Health Canada in accordance with the regulations and the Notice of Compliance with Conditions (NOC/c) Guidance.

  • Post-market Benefit-Risk Evaluation Reports-Confirmatory (PBRERs-C) for Bavencio, based on the following submission schedule:
    • every 6 months during the first 2 years following initial marketing authorization
    • annually thereafter for the following 2 years
    • every 3 years thereafter until such time as conditions associated with the market authorization are removed

    PBRERs-C should include an analysis of all adverse events as per the pharmacovigilance plan as well as safety updates including immunogenicity from all ongoing and future clinical trials with Bavencio.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

The programmed death ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating immune cells and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the programmed death 1 (PD-1) and B7.1 receptors found on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.

Avelumab, the medicinal ingredient in Bavencio, is a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against PD-L1. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the PD-1 and B7.1 receptors. This removes the suppressive effects of PD-L1 on cytotoxic CD8+ T cells, resulting in the restoration of antitumour T-cell responses. In syngeneic mouse tumour models, blocking PD-L1 activity resulted in decreased tumour growth.

As a fully human IgG1, avelumab retains Fcγ receptor binding and has been shown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.

A two-compartment population pharmacokinetic model was developed to describe avelumab concentration as a function of time, based on data from studies EMR100070-001, EMR100070-002 and EMR100070-003, representing a total of 1,629 subjects. The structural model was simple as it featured only a linear elimination from the central compartment.

The estimation of the terminal half-life in the population pharmacokinetic model differed by a factor of 1.5 from that in the non-compartmental analysis. The population pharmacokinetic analysis, when considering the entire therapeutic range, resulted in an estimate of 6 days, whereas after a single dose, the non-compartmental analysis estimate was 4 days. The ratio between the two estimates (6/4 = 1.5) was within the range of the ratios (1.6-1.8) between the minimum observed drug concentration (Cmin) values at the start and the end of the therapeutic cycle. Since the population pharmacokinetic analysis does not correct for accumulation of avelumab in Cmin, the half-life from this analysis might represent an artifact of the dosing regimen rather than an independent estimate. Both half-life estimates were included in the Bavencio Product Monograph.

The covariate of body weight had a positive correlation with the total systemic clearance (CL) and central volume of distribution (V1) parameters in the population pharmacokinetic model.

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

Clinical Efficacy

The clinical efficacy of Bavencio was evaluated in Part A of an ongoing pivotal Phase II, open-label, single-arm, multicenter trial, Study EMR100070-003 (Study 003 Part A), conducted in 88 patients with histologically confirmed metastatic Merkel cell carcinoma whose disease had progressed after at least one chemotherapy treatment for distant metastatic disease. The study excluded patients with: autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies; central nervous system metastases; infection with human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus; or an Eastern Cooperative Oncology Group (ECOG) performance score ≥2. Patients received Bavencio at a dose of 10 mg/kg via intravenous infusion every two weeks until disease progression or unacceptable toxicity.

Of the 88 patients, 73.9% were male, the median age was 72.5 years (range, 33 years to 88 years), 92% were Caucasian, and 55.7% and 44.3% had an ECOG performance status of 0 and 1, respectively. Thirty-five percent (35%) of patients had received two or more prior therapies, and 53% of patients had visceral metastases. All patients had tumour samples evaluated for PD-L1 expression. Of the evaluated tumour samples, 66% were PD-L1 positive (≥1% of tumour cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an investigational immunohistochemistry assay. Archival tumour samples from 77 patients were evaluated for Merkel cell polyomavirus using an investigational assay. Evidence of Merkel cell polyomavirus was found in 52% of the evaluated samples.

The primary efficacy endpoint of the pivotal Study EMR100070-003 was the confirmed best overall response according to the Response Evaluation Criteria in Solid Tumours (RECIST) (version 1.1), as determined by an Independent Endpoint Review Committee. The key secondary efficacy endpoint was duration of response. Progression-free survival and overall survival were also included in the efficacy assessment. The minimal follow-up period for the efficacy analyses was 12 months.

Best overall response was confirmed in 29 patients (33.0%, 95% confidence interval [CI]: 23.3, 43.8), and consisted of 10 complete responses (11.4%) and 19 partial responses (21.6%). Among the 29 patients with objective responses, median duration of response was not reached (range, 2.8 to 23.3+ months) at the time of data cut-off. Durable response (defined as 6 months or longer) was achieved in 25 patients (28.4%). A total of 21 patients remained in response at their last tumor assessment. Among those, 13 patients had a duration of response of at least 12 months.

The response to Bavencio treatment was observed in patients with tumour PD-L1 positive (≥1% tumour cells) or negative expression status, or with tumour positive or negative status for Merkel cell polyomavirus. However, both the PD-L1 and Merkel cell polyomavirus status of the tumours could not be considered reliable biomarkers for predicting treatment response because of small sample sizes and a high response variety, in addition to the experimental nature of the assay used for evaluating PD-L1 expression. The response to Bavencio treatment was also observed in patients with visceral metastasis or large tumour burden.

Median progression-free survival was 2.7 months (range, 0.03 to 24.5 months), (95% CI: 1.4, 6.9) and median overall survival was 12.9 months (range, 0.4 to 24.7 months), (95% CI: 7.5, not estimable). The results obtained for progression-free survival and overall survival have to be interpreted with caution and are considered of limited value due to the small number of patients enrolled in a study with a single-arm design.

Data were also submitted from the supportive Study 100070 Obs001 (Study Obs001), which was a retrospective, chart review and registry-based study to collect the treatment outcomes in patients with Merkel cell carcinoma treated with chemotherapy. Study Obs001 was intended to serve as a historical reference for the pivotal Study 003 Part A. A total of 686 patients with Merkel cell carcinoma were identified over a 10-year period in a United States health records database; 120 of whom were suspected to have metastatic disease. Thirty-nine (39) of the 120 patients had second-line chemotherapy. Among those, 14 patients were identified as similar to the patient population in Study 003 Part A and were included in the analysis. The overall response rate in these 14 patients was 28.6% (95% CI: 8.4, 58.1), with a median duration of response of 1.7 months (95% CI: 0.5, 3.0).

The efficacy data submitted from an early interim analysis of 16 treatment-naïve patients with metastatic Merkel cell carcinoma from the ongoing Study EMR100070-003 Part B were considered premature for an assessment. Consequently, Health Canada could not consider an indication of Bavencio for previously untreated patients with metastatic Merkel cell carcinoma.

In order to verify the clinical benefit of Bavencio, further follow-up is required, and further evaluation will take place upon the submission of the final report of the ongoing confirmatory trial, Study EMR100070-003 Part B (see What follow-up measures will the company take?).

Indication

The New Drug Submission for Bavencio was filed by the sponsor with the following indication:

  • Bavencio (avelumab) is indicated for the treatment of adult patients with metastatic Merkel Cell Carcinoma (MCC).

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. A caveat statement was also added to the indication, providing details regarding the limitations of the currently available data. Accordingly, Health Canada approved the following indication:

  • Bavencio (avelumab) is indicated for the treatment of metastatic Merkel Cell Carcinoma (MCC) in previously treated adults.
  • Marketing authorization with conditions was based on tumour response and durability of response.
  • An improvement in survival or disease-related symptoms has not yet been established.

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

Clinical Safety

The clinical safety of Bavencio was characterized in 88 patients with metastatic Merkel cell carcinoma, who participated in Part A of the pivotal EMR100070-003 study (Study 003 Part A) (described in the Clinical Efficacy section). Safety data were also derived from 1,650 patients with other solid tumours in an ongoing Study EMR 100070-001 (Study 001). Therefore, the safety database included pooled data from a total of 1,738 patients treated with the recommended therapeutic dose of Bavencio 10 mg/kg as an intravenous infusion every two weeks. In this population, 24% of patients were exposed to Bavencio for 6 months or longer, and 7% for 12 months or longer. Additionally, data from a small Phase I study, EMR100070-002 (Study 002) conducted in 17 Japanese patients with solid tumours were submitted and included in the safety assessment.

The most common (≥15%) adverse events in patients treated with Bavencio were fatigue, diarrhea, nausea, constipation, and decreased appetite. The most common adverse events and the severity of the adverse events were found to be consistent with the studied patient population.

A total of 911 patients died among the 1,783 patients (52.4%). Fifty percent (50%) of patients died in Study 003 Part A and 52.5% in Study 001. The majority of deaths (744 or 42.8%) were due to disease progression. Sixty-three patients (3.6%) died due to adverse events.

The primary safety risks associated with Bavencio were immune-mediated adverse drug reactions and infusion reactions.

In Study 003 Part A and Study 001, immune-mediated adverse drug reactions were reported in 17% and 14% of patients, and ≥Grade 3 immune-mediated adverse drug reactions occurred in 3.4% and 2.2% of patients, respectively.

Infusion reactions occurred in 21.6% and 25.5% of patients, and ≥Grade 3 infusion reactions were reported in 0% and 0.7% of patients in Study 003 Part A and Study 001, respectively.

The most common (≥1%) immune-mediated adverse drug reactions were hypothyroidism, pruritus, rash, and maculo-papular rash. No fatal case or Grade 4 immune-mediated adverse drug reactions were reported in Study 003 Part A. In Study 001, there were six immune-mediated fatal cases (autoimmune hepatitis, hepatic failure, pneumonitis, myocarditis, acute respiratory distress/failure) and two Grade 4 immune-mediated adverse drug reactions (autoimmune disorders and pneumonitis). Two patients (2.2%) in Study 003 Part A and 25 patients (1.7%) in Study 001 experienced serious immune-mediated adverse drug reactions including pneumonitis, autoimmune hepatitis, hypothyroidism, adrenal insufficiency, and autoimmune disorder. No additional safety issues were identified in Study 002. Overall, the incidence, severity and types of immune-mediated adverse drug reactions in Study 003 Part A, Study 001 and the pooled analysis are consistent with the safety profiles of other monoclonal antibody immune checkpoint inhibitors. Most immune-mediated adverse drug reactions were reversible and managed with dose interruption, administration of corticosteroids, and supportive care.

As with all therapeutic proteins, Bavencio has the potential for immunogenicity. Of the 1,738 patients treated with Bavencio at the recommended dose, 1,558 patients were evaluable for treatment-emergent anti-drug antibodies and 64 (4.1%) tested positive. Neutralizing antibodies were not tested.

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

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

In vitro pharmacology studies have demonstrated that avelumab, the medicinal ingredient in Bavencio, binds to human, mouse and cynomolgus monkey PD-L1 with comparable affinities. Avelumab can also bind to PD-L1 expressed on the surface of various human tumour cell lines. The in vivo antitumour activity of avelumab has been demonstrated in a syngeneic mouse model of colon cancer.

The toxicity of avelumab was evaluated in cynomolgus monkeys, in a 13-week repeat-dose toxicology study, followed by an 8-week recovery period. The dose of avelumab was 20-140 mg/kg/week administered intravenously. Local (injection site) toxicity was the major finding. The study did not report any notable effects on the male and female reproductive organs.

No reproductive or development toxicity studies have been conducted with avelumab. However, based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. In addition, animal studies have demonstrated that inhibition of the PD-1/PD-L1 signalling pathway can lead to increased risk of immune-mediated rejection of the developing fetus, resulting in fetal death.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Bavencio Product Monograph.

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

 

 

7.3 Quality Basis for Decision

 

Avelumab is a recombinant human IgG1 monoclonal antibody directed against human PD-L1. It consists of two heavy chains of 450 amino acid residues each and two light chains of 216 amino acid residues each with typical IgG1 inter- and intra-chain disulfide bonds.

Avelumab is a clear, colourless to slightly yellow concentrate for solution for infusion, practically free from visible particles. The pH of the solution is in the range of 5.0-5.6 and the osmolality is between 270 and 330 mOsm/kg. One single-use vial of 10 mL contains 200 mg of avelumab.

Characterization of the Drug Substance

Extensive characterization of the physicochemical, biological, and immunological properties of avelumab and confirmation of its purity were performed using methods selected in accordance with the International Council for Harmonisation (ICH) guidelines.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

Avelumab is produced in Chinese hamster ovary (CHO) cells using recombinant deoxyribonucleic acid (DNA) technology. The master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. These cell lines have been found to be genetically stable.

The drug substance manufacturing process consists of a series of steps: cell culture, harvest, purification, formulation and sterile filtration. The materials used in the manufacture of the drug substance are considered to meet standards appropriate for their intended use.

Process validation data from seven consecutive batches demonstrate that the drug substance manufacturing facility is able to consistently produce drug substance of acceptable quality.

The drug product manufacturing process consists of pooling of drug substance bags and mixing, followed by aseptic filling into vials, capping, visual inspection, labelling and packaging.

The sponsor has provided process validation data from five batches of drug product which demonstrate that the drug product manufacturing facility is able to consistently manufacture drug product of acceptable quality.

Results from characterization comparability studies support the changes made to the manufacturing process, formulation and avelumab concentration during pharmaceutical development.

The materials used in the manufacture of the drug product are considered to meet standards appropriate for their intended use.

Control of the Drug Substance and Drug Product

The sponsor has developed a control strategy that adequately reflects the quality of the drug substance and drug product. The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated and found to meet the drug product specifications and demonstrate consistency in manufacturing.

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 for Bavencio, when stored at 2°C to 8°C and protected from light, is considered acceptable.

The compatibility and integrity of the container closure system was demonstrated through compendial testing and stability studies. The container closure system is considered to be suitable for the drug product.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the avelumab drug substance has been successfully conducted by the Biologics and Genetic Therapies Directorate (BGTD), Health Canada.

An OSE of the facility involved in the manufacture and testing of Bavencio drug product was waived, as a successful OSE had previously been performed by the BGTD for another product at this site.

The sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The avelumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are validated and highly effective for their intended purpose.