Summary Basis of Decision for Herzuma

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 Herzuma is located below.

Recent Activity for Herzuma

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 Herzuma

Updated: 2024-02-08

The following table describes post-authorization activity for Herzuma, a product which contains the medicinal ingredient trastuzumab. 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 02480794 - 440 mg/vial trastuzumab, powder for solution, intravenous administration
  • DIN 02506211 - 150 mg/vial trastuzumab, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 264831

2022-06-03

Issued NOL 2022-08-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to increase the scale of the diluent manufacturing process and for a change in the drug product release or shelf‐life specifications. The submission was considered acceptable, and an NOL was issued.

NC # 260280

2022-01-12

Issued NOL 2022-02-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug product manufacturing process. The submission considered acceptable, and an NOL was issued.

SNDS # 237674

2020-04-08

Issued NOC 2021-04-16

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Herzuma (transtuzumab) in combination with pertuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

Drug product (DIN 02506211) market notification

Not applicable

Date of first sale: 2021-02-25

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

SNDS # 235644

2020-02-24

Issued NOC 2020-10-21

Submission filed as a Level I – Supplement for the addition of a new single-dose strength (150 mg/vial) supplied as a powder to be reconstituted in sterile water (not provided). The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02506211) was issued for the new strength.

NC # 234114

2019-12-03

Issued NOL 2020-02-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in cell bank/seed bank qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02480794) market notification

Not applicable

Date of first sale: 2019-12-11

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

SNDS # 227400

2019-05-16

Issued NOC 2019-09-03

Submission filed as a Level I - Supplement to update the labelling and package insert. The submission was reviewed and considered acceptable, and an NOC was issued.

NDS # 210238

2017-10-24

Issued NOC

2019-09-03

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Herzuma

Date SBD issued: 2020-04-29

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

Trastuzumab

Drug Identification Number (DIN):

  • DIN 02480794 - 440 mg/vial, powder for solution, intravenous administration

Celltrion Healthcare Co., Ltd.

New Drug Submission Control Number: 210238

 

On September 3, 2019, Health Canada issued a Notice of Compliance (NOC) to Celltrion Healthcare Co., Ltd for Herzuma, a biosimilar to Herceptin (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as Subsequent Entry Biologics in Canada. Both Herzuma and Herceptin contain highly similar versions of the medicinal ingredient, trastuzumab.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Herceptin is the reference biologic drug. Similarity between Herzuma and Herceptin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Herzuma for all of the indications that are currently authorized for Herceptin except the use in combination with Perjeta (pertuzumab) and docetaxel for untreated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit-risk profile of Herzuma is considered to be highly similar to the reference biologic drug for various indications relating to the following conditions:

  • Early Breast Cancer
    • Herzuma (trastuzumab) is indicated for the treatment of patients with early stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress HER2,
      • Following surgery and after chemotherapy
      • Following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
      • In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
  • Metastatic Breast Cancer
    • Herzuma is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.
  • Metastatic Gastric Cancer
    • Herzuma in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

 

1 What was approved?

 

Herzuma, an antineoplastic drug, was authorized for the following indications (which include relevant caveat statements):

  • Early Breast Cancer
    • Herzuma (trastuzumab) is indicated for the treatment of patients with early stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress HER2,
      • Following surgery and after chemotherapy
      • Following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
      • In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
  • Metastatic Breast Cancer
    • Herzuma is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.
  • Metastatic Gastric Cancer
    • Herzuma in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

The safety and effectiveness of trastuzumab in pediatric patients have not been established.

The reported clinical experience is not adequate to determine whether older patients (aged 65 years or older) respond differently to trastuzumab treatment than younger patients.

Herzuma is a biosimilar to Herceptin (United States licensed Herceptin; herein referred to as Herceptin). Both drugs contain the medicinal ingredient trastuzumab, a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is directed against the extracellular domain of the HER2. Trastuzumab binds to the HER2 on the surface of cancer cells and inhibits their proliferation.

Similarity between Herzuma and the reference biologic drug, Herceptin has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, two comparative pharmacokinetic studies (CT P6 1.5 and CT P6 1.4), and one comparative efficacy and safety clinical trial (CT P6 3.2).

Herzuma is contraindicated in patients with known hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Herzuma 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.

Herzuma (trastuzumab 440 mg/vial) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains L histidine, L histidine hydrochloride, polysorbate 20, and trehalose dihydrate.

For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical for Decision sections.

Additional information may be found in the Herzuma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Herzuma approved?

 

Health Canada considers that the benefit-risk profile of Herzuma is highly similar to the reference biologic drug Herceptin for the treatment of HER2-positive early breast cancer, HER2-positive metastatic breast cancer, and HER2-positive metastatic gastric cancer. Similarity between Herzuma and Herceptin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The New Drug Submission (NDS) filed for Herzuma requested authorization for all of the indications and clinical uses that are currently authorized for Herceptin except the use in combination with Perjeta (pertuzumab) and docetaxel for untreated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The indications have been authorized on the basis of demonstrated similarity between Herzuma and the reference biologic drug.

Breast cancer is the third most frequently diagnosed cancer in Canada, representing approximately 13% of all cases. While the prevalence of gastric cancer is relatively lower, an estimated 43.5% of cases are diagnosed at stage IV. Current treatment options include surgery, radiation therapy, hormonal therapy, chemotherapy, and targeted therapy. Factors affecting the choice of treatments include the stage of the cancer, hormone receptor (HR) status (for breast cancer), HER2 status, and overall health of the patient.

Based on comparative structural and functional studies, Herzuma and Herceptin were judged highly similar in terms of quality attributes.

To support the clinical comparability of Herzuma to Herceptin, the sponsor provided evidence of pharmacokinetic similarity of Herzuma and Herceptin in healthy male volunteers. Data from two comparative pharmacokinetic studies were provided, Study CT P6 1.5 (Primary study) and Study CT-P6 1.4 (Pilot study). The results from both studies demonstrated comparable pharmacokinetics between Herzuma and Herceptin.

In addition, a comparative clinical efficacy and safety study (CT P6 3.2) evaluated Herzuma and Herceptin in patients with HER2-positive early breast cancer and ruled out clinically meaningful differences in safety and efficacy between the biosimilar and the reference biologic drug. The demonstration of similarity based on the comparative structural and functional, non-clinical, and clinical studies enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

As for safety, Herzuma has demonstrated a comparable safety profile with its reference biologic product, Herceptin. As such, the Adverse Reactions section of the Herzuma Product Monograph is based on the clinical experience with the reference biologic drug, Herceptin. Furthermore, as with Herceptin, a Serious Warnings and Precautions box has been included in the Herzuma Product Monograph to highlight the following serious risks: cardiotoxicity, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity.

A Risk Management Plan (RMP) for Herzuma was submitted by Celltrion Healthcare Co., Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look alike Sound alike brand name assessment was performed and the proposed name Herzuma was accepted.

Overall, the therapeutic benefits of Herzuma are expected to be similar to the known benefits of the reference biologic drug, Herceptin, and are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Herzuma Product Monograph to address the identified safety concerns.

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 Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

 

3 What steps led to the approval of Herzuma?

 

Submission Milestones: Herzuma

Submission Milestone Date
Pre-submission meeting: 2017-03-02
Submission filed: 2017-10-24
Screening  
Screening Acceptance Letter issued: 2017-11-17
Review  
Review of Risk Management Plan complete: 2018-06-14
Quality Evaluation complete: 2018-09-05
Clinical Evaluation complete: 2018-09-13
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-09-13
Patent Hold  
Submission placed on Patent Hold: 2018-09-13
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2019-09-03

 

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?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The onus is on the Herzuma sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug (Herceptin) for safety signals that could impact the biosimilar, and make safety updates to the Herzuma Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

 

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

 

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 decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Herzuma 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:

 

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

 

Herzuma was developed as a biosimilar to the reference biologic drug Herceptin (United States licensed Herceptin; herein referred to as Herceptin). For biosimilars, the weight of evidence is provided by structural and functional studies. In addition to the standard chemistry and manufacturing data package usually submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

Comparative Structural and Functional Studies

A two-way similarity assessment was conducted using lots of Herceptin and Herzuma, using physicochemical and biological comparisons. The biosimilarity study evaluated a variety of attributes including physicochemical properties, biological activity, purity and impurity profiles, and stability profiles including forced degradation conditions. Attributes were assessed based on the potential impact to biological activity, pharmacokinetics, pharmacodynamics, efficacy, immunogenicity, and/or safety.

The results from the biosimilarity assessment demonstrated that Herzuma is identical with respect to primary sequence and is highly similar with regards to higher order structures, charge variants, protein content, potency and other physical properties. Some minor distinctions were identified, but are not expected to result in clinically meaningful differences. The comparative stability and forced degradation results demonstrated that Herzuma and Herceptin are sensitive to the same degradation pathways with similar rates of breakdown when exposed to different stress conditions. Together, these results indicate that Herzuma and Herceptin are highly similar.

Characterization of the Drug Substance

Trastuzumab is a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody with two identical heavy chains and two identical light chains, covalently linked with four inter-chain disulfide bonds. The molecular weight of trastuzumab is approximately 148 kDa. The antibody binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 (HER2).

Detailed characterization studies were performed to provide assurance that trastuzumab consistently exhibits the desired characteristic structure and biological activity.

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 and acceptable limits.

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

The drug substance trastuzumab is produced by recombinant deoxyribonucleic acid (rDNA) technology in a mammalian expression system (Chinese hamster ovary [CHO] cell line). The final cell culture is harvested, clarified and subsequently purified using a series of chromatographic steps. Viral inactivation and clearance is achieved by low pH and nanofiltration. Following purification, the bulk drug substance is filtered into the drug substance containers.

The drug product is manufactured using common methodologies for the production of aseptic protein products. The drug product manufacturing process consists of formulation of drug substance, filtration, aseptic filling, lyophilization, capping and visual inspection.

Herzuma is supplied as a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous administration. Each vial of Herzuma contains 440 mg trastuzumab, 6.4 mg L-histidine, 9.9 mg L-histidine hydrochloric acid, 1.8 mg polysorbate 20, and 879 mg α, α-trehalose dihydrate. Prior to use, each vial of Herzuma should be reconstituted with either 20 mL of bacteriostatic water for injection (BWFI) to yield a multi-dose solution, or 20 mL of sterile water for injection (sWFI) to be used as a single dose solution for immediate use. The reconstituted solution contains 21 mg/mL trastuzumab, at a pH of approximately 6. The BWFI is supplied along with the drug product, and contains 1.1% benzyl alcohol as a preservative.

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

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the trastuzumab with the excipients is supported by the stability data provided.

Control 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 International Council for Harmonisation guidelines.

Through Health Canada's lot release testing and evaluation program, 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 shelf life for Herzuma is considered acceptable when stored at the recommended temperature of 2ºC to 8°C.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.

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.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the facilities involved in the manufacture and testing of the drug substance and the drug product were not deemed necessary.

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

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) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy and are therefore considered suitable for the production of Herzuma.

 

7.2 Non-Clinical Basis for Decision

 

For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

The non-clinical database submitted for Herzuma complies with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

In a number of in vitro binding and functional assays reflective of the mechanism of action of trastuzumab, Herzuma was shown to have similar biological activity to Herceptin.

One comparative repeat-dose toxicological study (Study ZIP0014) conducted in cynomolgus monkeys demonstrated no notable differences between Herzuma and Herceptin for either pharmacokinetic or toxicological endpoints.

The non-clinical findings are supportive of similarity between Herzuma and Herceptin.

The results of the comparative non-clinical studies have been included in the Herzuma Product Monograph. In view of the intended use of Herzuma, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Clinical basis for decision

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetic Studies

To support the clinical comparability of Herzuma to Herceptin the sponsor provided evidence of pharmacokinetic similarity of Herzuma and Herceptin in healthy male volunteers. Data from two comparative pharmacokinetic studies were provided, Study CT-P6 1.5 (Primary study) and Study CT-P6 1.4 (Pilot study).

Study CT-P6 1.5

This was a randomized, double-blind, two-arm, parallel group, single-dose study which compared the pharmacokinetics of Herzuma to Herceptin in healthy adult male subjects. Secondary objectives of this study were to compare the safety and immunogenicity of the two products, Herzuma and Herceptin.

Seventy (70) subjects were enrolled in the study and randomized in a 1:1 ratio to one of two treatment arms, to receive a single dose 6 mg/kg Herzuma or Herceptin via intravenous infusion. During that time, serum samples were collected up to Day 71 during which the pharmacokinetic, safety, and immunogenicity assessments were made.

Comparative pharmacokinetics was evaluated by assessing the area under the serum-concentration-time curve from time 0 to the last quantifiable concentration (AUCT), the area under the serum-concentration-time curve from time 0 to infinity (AUCI), and the maximum concentration (Cmax), which were calculated for both Herzuma and Herceptin. Results obtained from the analysis showed the 90% confidence intervals (CI) for the geometric least squares mean ratios of AUCT, AUCI, and Cmax were contained within the predefined equivalence margin of 80.0% to 125.0%, indicating comparable pharmacokinetics between Herzuma and Herceptin. The ratio (90% CI) of geometric means (Herzuma vs. Herceptin) for AUCT, AUCI, and Cmax were 99.3% (92.9, 106.2), 99.1% (93.0, 105.5), and 96.6% (90.9, 102.6), respectively. The mean secondary pharmacokinetic endpoints (Tmax and T1/2) were similar between the Herzuma and Herceptin treatment arms.

In terms of safety, despite limited safety information there were no clinically meaningful differences between the two treatment arms. In addition, none of the subjects tested positive for anti-drug antibodies (ADAs) at any time point.

Study CT-P6 1.4

This was a randomized, double-blind, two-arm, parallel group, single-dose study which compared the pharmacokinetics of Herzuma to Herceptin in healthy adult male subjects. The CT-P6 1.4 had a similar design to Study CT-P6 1.5, with the exception of a shorter study duration of 42 days.

Results from the CT-P6 1.4 study also demonstrated comparable pharmacokinetics between Herzuma and Herceptin. The ratio (90% CI) of geometric means (Herzuma vs. Herceptin) for AUCT and Cmax were 96.5% (88.8, 104.9) and 97.2% (89.1, 106.0), respectively. Therefore, the 90% CI of ratio of geometric means for both AUCT and Cmax were entirely contained within the predefined equivalence margin of 80.0% to 125.0%, indicating comparable pharmacokinetics.

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

Comparative Clinical Efficacy, Safety, and Immunogenicity

The comparative clinical efficacy, safety, and immunogenicity of Herzuma and Herceptin were primarily evaluated in a Phase III, multicentre, double-blind, randomized, parallel-group, active-controlled study, CT-P6 3.2. This study compared the efficacy, safety, and immunogenicity of Herzuma versus Herceptin, as neoadjuvant and adjuvant treatment in patients with HER2-positive early breast cancer.

Study CT-P6 3.2

The study was conducted in patients with HER2-positive operable early breast cancer.

A total of 562 patients were randomly assigned to one of two treatment groups in the intent-to-treat (ITT) set (278 patients and 284 patients in the Herzuma and Herceptin arms, respectively). Demographic and baseline disease characteristics were generally similar between the Herzuma and Herceptin arms.

During the Neoadjuvant Period, patients received either Herzuma or Herceptin at an initial dose of 8 mg/kg administered by a single intravenous infusion on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycles 2 through 8 (3-week cycles). Patients also received docetaxel (75 mg/m2) during Cycles 1 through 4 and FEC (5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2) during Cycles 5 through 8. Docetaxel and FEC were administered on the day of Herzuma or Herceptin administration (Day 1, 3-week cycles).

After a total of 8 treatment cycles of the neoadjuvant treatment, surgery (lumpectomy or mastectomy) including axillary lymph node assessment (sentinel lymph node biopsy or axillary lymph node dissection) was performed within 3 to 6 weeks from the last dose of study drug in the Neoadjuvant Period.

Three to 6 weeks after surgery, patients entered the Adjuvant Period and received 6 mg/kg of Herzuma or Herceptin as randomized, repeated every 3 weeks for up to 1 year from the first day of study drug administration in the Neoadjuvant Period, excluding surgery (or up to 10 cycles after surgery).

Comparative Clinical Efficacy

The primary efficacy endpoint was the proportion of subjects achieving pCR, defined as the absence of invasive tumor cells in the breast and in axillary lymph nodes, regardless of ductal carcinoma in situ. The pathological response was evaluated at the time of surgery with resected specimen by local pathologists. In the ITT set, the pCR rate was 43.2% (95% CI: 37.3- 49.2) in the Herzuma arm and 47.2 (95% CI: 41.3-53.2) in the Herceptin arm, with a risk ratio (RR) of 0.9. The 95% CI for the RR was 0.8-1.1, which is within the pre-defined equivalence margin of 0.7-1.4.

The neoadjuvant indication in early breast cancer is not authorized in Canada for Herceptin. However, this treatment is included in the guidelines issued by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). The neoadjuvant setting is considered a suitable model for the detection of potential difference between the biosimilar and the reference biologic product Herceptin, especially given that the early breast cancer population is a relatively homogeneous population, and that pCR is considerably a sensitive endpoint in the early breast cancer setting. In particular, sensitivity is important for testing any clinically meaningful difference that may exist in the context of an equivalence study for a proposed biosimilar.

Comparative Clinical Safety

Overall, Herzuma was well tolerated and the safety profile of Herzuma was similar to that of Herceptin.

The number of patients who experienced at least one treatment-emergent adverse event (TEAE) was similar between the two treatment groups (97.0% in the Herzuma arm and 95.3% in the Herceptin arm) over the course of the study. The TEAEs most frequently reported for patients in the Herzuma treatment group were alopecia (195 [72.0%] patients), nausea (99 [36.5%] patients), and neutropenia (97 [35.8%] patients). The TEAEs most frequently reported for patients in the Herceptin treatment group were alopecia (213 [76.6%] patients), neutropenia (116 [41.7%] patients), and nausea (94 [33.8%] patients).

The incidence of Grade ≥3 TEAEs and serious TEAEs were comparable between the 2 treatment arms. Grade 3 TEAEs were reported in 26.9% of patients in the Herzuma arm and 23.7% in the Herceptin arm; Grade 4 TEAES in 11.1% in the Herzuma arm and 15.8% in the Herceptin arm; two Grade 5 events occurred in each arm. Serious adverse events were reported in 7.4% of patients in the Herzuma arm and 11.9% in the Herceptin arm.

In Study CT-P6 3.2, a decrease in left ventricular ejection fraction (LVEF) to a value of 10 points from the baseline value and below an absolute value of 50% was defined as a heart failure event, and considered as an adverse event of special interest (AESI). Patients who experienced at least one heart failure defined as an AESI during the study were 3.7% and 2.5% in the Herzuma and Herceptin arms, respectively.

Taken together, the safety profiles of the two products are considered comparable.

Comparative Immunogenicity

In Study CT-P6 3.2, 12 patients (4 [1.5%] in the Herzuma arm and 8 [2.9%] in the Herceptin arm) had positive anti-drug antibody (ADA) results at the baseline. However, results for neutralizing antibody were all negative. No positive (ADA) result at post-baseline visits was reported throughout the study in either arm. This is consistent with historical data, which indicates that trastuzumab has low immunogenic potential.

Conclusion

Overall, the safety profile of Herzuma is considered to be comparable to that which has been established for the reference biologic drug Herceptin. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Herzuma Product Monograph, as they are in the Product Monograph for Herceptin.

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

Indications

Herzuma is considered to be biosimilar to Herceptin, the reference biologic drug. Herceptin is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Herceptin is authorized in Canada are HER2-positive early stage breast cancer, HER2-positive metastatic breast cancer, and HER2-positive metastatic gastric cancer.

Within this drug submission, the sponsor requested the authorization of Herzuma for all of the indications that are currently authorized for Herceptin except the combination with Perjeta (pertuzumab) and chemotherapy in the treatment of metastatic breast cancer. Upon Health Canada's review, Herzuma was authorized for the treatment of the following diseases (the indications include relevant caveat statements):

  • Early Breast Cancer
    • Herzuma (trastuzumab) is indicated for the treatment of patients with early stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress HER2,
      • Following surgery and after chemotherapy
      • Following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
      • In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
  • Metastatic Breast Cancer
    • Herzuma is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.
  • Metastatic Gastric Cancer
    • Herzuma in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Similarity between Herzuma and Herceptin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Herzuma and the reference biologic drug Herceptin, in structural, functional, non-clinical, and clinical studies.

 

 

 

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