Summary Basis of Decision for Enhertu

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 Enhertu is located below.

Recent Activity for Enhertu

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.

The following table describes post-authorization activity for Enhertu, a product which contains the medicinal ingredient trastuzumab deruxtecan. 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.

Updated: 2025-05-30

Drug Identification Number (DIN):

DIN 02514400 – 100 mg/vial trastuzumab deruxtecan, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 288030

2024-06-25

Issued NOC 2025-04-04

Submission filed as a Level I – Supplement for the addition of a drug substance manufacturing site and a change in scale of the manufacturing process at the fermentation stage. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 285834

2024-04-10

Issued NOC under NOC/c Guidance 2025-01-17

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Enhertu (trastuzumab deruxtecan) as monotherapy is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. The submission was reviewed and considered acceptable, and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c). A Regulatory Decision Summary was published.

SNDS-C # 275831

2023-06-01

Issued NOC 2024-07-09

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 SNDS-C was submitted to fulfill the conditions outlined in the Letter of Undertaking (LOU) dated March 11, 2012, issued under NDS # 242104. The sponsor provided the results of DESTINY-Breast02. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued April 15, 2021. 

SNDS # 274652

2023-04-24

Issued NOC 2024-04-10

Submission filed as a Level I – Supplement to update the PM with an updated analysis of study DESTINY-Breast03 in accordance with the post-decision commitment dated June 17, 2022 issued under SNDS #259440. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

PBRER-C # 272760

2023-02-24

Filed 2024-02-14

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 2021-12-20 to 2022-12-19. The information was reviewed and found acceptable. No further action was required.

NC # 274327

2023-04-11

Issued NOL 2023-05-24

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 considered acceptable, and an NOL was issued.

SNDS # 265333

2022-06-17

Issued NOC 2023-01-06

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: Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Patients with hormone receptor positive (HR+) breast cancer should have received at least one and be no longer considered eligible for endocrine therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 267527

2022-09-01

Cancellation Letter Received 2023-01-03

Submission filed as a Level I – Supplement to eliminate the package insert leaflet containing dosing, reconstitution, and administration information and to update the inner and outer labels to reflect this change. Health Canada determined that the package insert remains a regulatory requirement for labelling, and access by patients is important for the management of Enhertu-related toxicities. The submission was cancelled by the sponsor.

SNDS # 264445

2022-05-20

Issued NOC 2022-12-22

Submission filed as a Level I – Supplement for the addition of an alternative drug substance manufacturing site. The data were reviewed and considered acceptable, and an NOC was issued.

SNDS # 259440

2021-12-10

Issued NOC 2022-06-15

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: Enhertu (trastuzumab deruxtecan for injection) as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least one prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 254244

2021-06-28

Issued NOC 2021-11-19

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 Part III: Patient Medication Information and to the package insert. An NOC was issued.

Drug product (DIN 02514400) market notification

Not applicable

Date of first sale 2021-07-09

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

NDS # 242104

2020-07-24

Issued NOC under NOC/c Guidance 2021-04-15

NOC issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c) for New Drug Submission.
Summary Basis of Decision (SBD) for Enhertu

Date SBD issued: 2021-07-09

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

Trastuzumab deruxtecan

Drug Identification Number (DIN):

  • DIN 02514400 - 100 mg/vial trastuzumab deruxtecan, powder for solution, intravenous administration

AstraZeneca Canada Inc.

New Drug Submission Control Number: 242104

 

On April 15, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to AstraZeneca Canada Inc. for the drug product Enhertu. 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 Enhertu is favourable for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1). The indication is authorized based on tumour response rate and durability of response. An improvement in survival has not been established.

 

1 What was approved?

 

Enhertu, an antineoplastic agent, was authorized for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1).  The indication is authorized based on tumour response rate and durability of response. An improvement in survival has not been established.

Enhertu is not authorized for use in pediatric patients (<18 years of age) as no data are available to Health Canada in this population.

No clinically relevant differences in efficacy were observed in geriatric patients (≥65 years of age) compared to younger patients in clinical studies. Evidence from clinical studies suggests the use of Enhertu in the geriatric population is associated with differences in safety.

Enhertu 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.

Enhertu 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.

Enhertu (100 mg/vial trastuzumab deruxtecan) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, and sucrose.

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

 

2 Why was Enhertu approved?

 

Health Canada considers that the benefit-risk profile of Enhertu is favourable for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1).

Enhertu was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Unresectable or metastatic HER2-positive breast cancer is a serious, life-threatening disease. It is generally incurable and the treatment goal is to improve duration and/or quality of life. In Canada, approximately 20% of breast cancers are HER2-positive. The first line treatment for the disease is pertuzumab, trastuzumab, and docetaxel. The second line treatment is T-DM1. At the time of the initiation of the pivotal clinical study for Enhertu, there was no standard treatment to follow T-DM1. Available therapies after T-DM1 include a number of combination regimens that generally consisted of a HER2-directed agent (e.g., lapatinib, trastuzumab) and a non-cross-resistant chemotherapy agent, however, the effectiveness of these available therapies is not satisfactory.

Enhertu (trastuzumab deruxtecan) is a HER2-targeted antibody drug conjugate composed of three components:

  1. a humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody with the same amino acid sequence as trastuzumab, covalently linked to
  2. a cytotoxic topoisomerase I inhibitor, via
  3. a tetrapeptide-based cleavable linker.

Deruxtecan is composed of the topoisomerase I inhibitor and the linker. Following binding to HER2 on tumour cells, Enhertu undergoes internalization and intracellular linker cleavage. Upon release, the membrane permeable topoisomerase I inhibitor causes deoxyribonucleic acid (DNA) damage and apoptotic cell death.

Enhertu has demonstrated efficacy as monotherapy in adult patients with unresectable or metastatic HER2-positive breast cancer after prior treatment with T-DM1. The market authorization with conditions was based on data from the pivotal, Phase II, multicentre, non-controlled Study U201.The primary efficacy endpoint was the confirmed objective response rate based on independent central review. A key secondary endpoint was duration of response. In 184 patients who were enrolled to receive Enhertu 5.4 mg/kg every 3 weeks, the objective response rate was 60.9% (95% confidence interval [CI]: 53.4, 68.0). The median duration of response was 14.8 months (95% CI: 13.8, 16.9). In the context of the recommended condition of use and the available treatment options, Health Canada considers these efficacy results as promising evidence of clinical effectiveness. The clinical benefit of Enhertu is to be confirmed in the ongoing Phase III clinical Study U301 which compares Enhertu 5.4 mg/kg every three weeks with an investigator’s choice comparative therapy in a patient population similar to that of Study U201.

The safety of Enhertu was evaluated in a pooled analysis of 234 patients with HER2-positive unresectable or metastatic breast cancer who received at least one dose of Enhertu at 5.4 mg/kg in the pivotal Study U201 and the supportive Study J101. The most common adverse reactions (occurring with a frequency ≥20%) were: nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutrophil count decreased, diarrhea, cough, leukopenia, headache, and platelet count decreased. Serious adverse reactions occurred in 20% of patients. Serious adverse reactions that occurred in >1% of patients were interstitial lung disease, vomiting, nausea, and hypokalemia. Fatalities due to adverse events occurred in 5.1% of patients, including 2.6% of patients who developed interstitial lung disease.

Appropriate warnings and precautions are in place in the Enhertu Product Monograph to address the identified key safety concerns. The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph: interstitial lung disease and pneumonitis, embryo-fetal toxicity, and the risk of medication errors between Enhertu (trastuzumab deruxtecan) and trastuzumab or trastuzumab emtansine (TDM-1).

Additional safety data will be assessed when the results of the Phase III Study U301 are submitted, as part of the conditions under the NOC/c Guidance.

A Risk Management Plan (RMP) for Enhertu was submitted by AstraZeneca Canada Inc. to Health Canada. 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. Upon review, the RMP was revised. The updated RMP was considered acceptable.  

As an additional risk minimization measure, in order to mitigate the risk of interstitial lung disease in the post-market setting, the sponsor proposed education materials for both healthcare professionals and patients, as well as a Patient Alert Card for patients. The purpose of the Patient Alert Card is to remind the patient of the key symptoms of lung problems that need to be reported immediately to healthcare professionals in order to facilitate early detection and treatment of interstitial lung disease. These additional risk mitigation measures are considered acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Enhertu Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.

A review of the submitted brand name assessment was conducted which included testing for look-alike sound-alike attributes. The proposed name Enhertu was accepted.

Overall, the therapeutic benefits of Enhertu therapy seen in the pivotal study are promising and are considered to outweigh the potential risks. Enhertu has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Enhertu Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Enhertu 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 Enhertu?

 

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 Enhertu. An assessment was conducted and it was determined that there was promising evidence of clinical effectiveness that the drug has the potential to provide:

  1. Effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada, or
  2. 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.

Subsequent review led to the decision to issue the sponsor market authorization under the 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.

The New Drug Submission (NDS) for Enhertu was reviewed under Project Orbis, an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Enhertu was classified as a Project Orbis Type C submission, where the United States Food and Drug Administration (FDA) had already issued a positive decision and subsequently shared their completed review documents with Health Canada. The Canadian regulatory decision on the review of Enhertu was made independently and was based on a critical assessment of the data package submitted to Health Canada. The foreign multidisciplinary review completed by the United States FDA was used as an added reference.

In addition, the European Medicines Agency's comments, questions, and decision were shared by the sponsor during the review.

 

Submission Milestones: Enhertu

Submission Milestone Date
Pre-submission meeting (Clinical only) 2020-04-07
Pre-submission meeting (Quality only) 2020-06-29
Request for priority status  
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance 2020-05-28
Submission filed 2020-07-24
Screening  

Screening Acceptance Letter issued

 2021-08-21
Review  

Non-Clinical Evaluation complete

 2021-01-15

Review of Risk Management Plan complete

 2021-02-01

Quality Evaluation complete

 2021-03-02

Labelling Review complete

 2021-03-08

Clinical/Medical Evaluation complete

 2021-03-09

Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued

 2021-03-09
Review of Response to NOC/c-QN:  

Response filed (Letter of Undertaking)

 2021-03-11

Clinical/Medical Evaluation complete

 2021-03-30

Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate/Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance

 2021-04-15

 

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

 

4 What follow-up measures will the company take?

 

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the final clinical study report for Study U301, a Phase III, multicentre, randomized, open-label, active-controlled study of trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2)-antibody drug conjugate, versus treatment with investigator’s choice for HER2-positive, unresectable and/or metastatic breast cancer patients previously treated with trastuzumab emtansine (T-DM1) to confirm the clinical benefit of Enhertu. It is anticipated that the final report will be available in the third quarter of 2023.

As part of the marketing authorization for Enhertu, Health Canada requested and the sponsor agreed to additional conditions which include (but are not limited to):

  • Discussing with Health Canada the use of HER2 biomarker testing in blood samples to support future Enhertu submissions as appropriate.
  • Monitoring and analysing immunogenicity and the risk of QT prolongation in ongoing Enhertu clinical studies. Monitoring in the post-marketing setting will be conducted through routine pharmacovigilance processes.
  • Monitoring and analysing Enhertu safety in patients with moderate hepatic impairment or those with moderate or severe renal impairment in ongoing and future clinical studies until sufficient data are generated on the benefit/risk assessment for this patient population. In the next regulatory submission for Enhertu, AstraZeneca Canada Inc. will provide an integrated analysis for patients with liver and kidney impairment using pharmacokinetic parameters from a noncompartmental analysis.

 

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

 

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 life cycle.

The PAAT for Enhertu 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 Clinical Basis for Decision

 

Enhertu (trastuzumab deruxtecan) is a HER2-targeted antibody drug conjugate composed of three components:

  1. a humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, covalently linked to
  2. a cytotoxic topoisomerase I inhibitor, via
  3. a tetrapeptide-based cleavable linker.

Deruxtecan is composed of the topoisomerase I inhibitor and the linker. Enhertu exhibits HER2-specific antitumor activity via a mechanism of action that combines mAb specificity with broad cytotoxicity of the released drug. After binding to the HER2 extracellular domain of the target tumor cells, Enhertu is internalized and cleaved by lysosomal enzymes preferentially expressed in tumour cells. The membrane permeable topoisomerase I inhibitor component of the released drug causes deoxyribonucleic acid (DNA) damage and apoptotic cell death. In addition, Enhertu has HER2-mediated protein kinase B (Akt) phosphorylation inhibition and antibody dependent cellular cytotoxic (ADCC) activity through the monoclonal antibody.

The pharmacokinetics of trastuzumab deruxtecan and its released active metabolite (MAAA-1181a) were characterized in five clinical studies. The intravenous administration of trastuzumab deruxtecan resulted in an unintended but low plasma level of the released cytotoxic drug, which was directly proportional to the amount of trastuzumab deruxtecan infused.

A population pharmacokinetic analysis consisted of a two-compartment model of the intact drug, providing a pseudo-subcutaneous injection into a one-compartment model of the active metabolite, with linear and time-varying elimination. The Nonlinear Mixed Effects Modeling (NONMEM) program exhibited large shrinkage in some of the parameters, therefore the final model was considered too rudimentary to support the determination of the recommended dose regimen of 5.4 mg/kg every 3 weeks. The recommended dose was primarily supported by efficacy and safety data.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity, meaning the development of anti-drug antibodies (ADAs) which have the potential to neutralize the biological activity of the drug. The incidence of ADA was low. Four (0.6%) patients experienced treatment-emergent ADA. The impact of ADA on the pharmacokinetics of trastuzumab deruxtecan and MAAA-1181a is unknown due to limited number of patients with positive ADA. 

QT Prolongation

In a Phase I, open-label, single-arm study of Enhertu administered to patients (n = 49) with unresectable and/or metastatic HER2-expressing breast cancer, no large mean increase from baseline in QTc interval (i.e., >20 ms) was detected following treatment with Enhertu at 6.4 mg/kg every 3 weeks (1.2-fold higher than recommended dose) on Cycle 1 or Cycle 3, 7 hours post dose.

In a separate study (Study A104), 2/40 (5.0%) of patients had a QTc increase >30 ms during the study and no patients in either cohort had a QTc increase >60 ms. One (2.5%) patient experienced a QTcF >480 ms. This is considered a clinically significant finding for patients administered with 5.4 mg/kg dose regimen.

The sponsor has been requested to monitor and analyze the risk of QT prolongation in ongoing Enhertu clinical studies and in the post-market setting.

Drug-Drug Interactions

Ritonavir and itraconazole did not affect the exposure metrics of Enhertu or the released topoisomerase I inhibitor.

No dose adjustment is required during coadministration of Enhertu with drugs that are inhibitors of organic anion transporting polypeptide 1B (OATP1B) or cytochrome P450 (CYP) 3A.

The clinical pharmacological data support the use of Enhertu for the recommended indication. For further details, please refer to the Enhertu Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy and safety of Enhertu for the treatment of adult patients with human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic breast cancer after treatment with trastuzumab emtansine (T-DM1) was evaluated in the pivotal Phase II Study U201 and the supportive Phase I Study J101.

Pivotal Study

The pivotal Study U201 was a Phase II, two-part, multicentre, open-label study conducted in 253 patients enrolled and treated at one of the seventy-two study sites in Asia, Europe, and the United States. This two-part study was designed to justify the recommended dose of Enhertu and to further investigate its safety and efficacy in patients with unresectable and/or metastatic HER2-positive breast cancer previously treated with T-DM1. Part 1 of the study was randomized and consisted of two stages: a pharmacokinetic stage and a dose-finding stage. Part 2 was nonrandomized, and all patients received Enhertu at the recommended dose determined in Part 1.

The study enrolled adult patients with unresectable or metastatic HER2-positive breast cancer who had received prior treatment with T-DM1. Patients had received two or more prior anti-HER2 regimens, including T-DM1 (100%), trastuzumab (100%), and pertuzumab (65.8%). Archival breast tumor samples were required to show HER2 positivity defined as HER2 immunohistochemistry (IHC) 3+ or in-situ hybridization (ISH)-positive. The study excluded patients with a history of treated interstitial lung disease or interstitial lung disease at screening, patients with untreated, symptomatic brain metastases, and patients with a history of clinically significant cardiac disease. Enhertu was administered by intravenous infusion at 5.4 mg/kg once every 3 weeks until disease progression, death, withdrawal of consent, or unacceptable toxicity.

The baseline demographic and disease characteristics of patients included in the study were: median age 55 years (range: 28 to 96); female (100%); White (54.9%), Asian (38.0%), Black or African American (2.2%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (55.4%) or 1 (44.0%); hormone receptor status (positive: 52.7%); presence of visceral disease (91.8%); stable brain metastases (13%); median number of prior therapies in the metastatic setting: 5 (range: 2 to 17); sum of diameters of target lesions (<5 cm: 42.4%, ≥5 cm: 50.0%). The demographics and baseline disease characteristics of the patients included in the study were considered to be generally representative of Canadian patients, with the exception that enrolled patients tended to have good performance status and less significant comorbidities as a result of meeting the study eligibility criteria. Male patients were eligible as per the protocol, but were not enrolled in the study, likely due to the relatively low incidence of breast cancer in male patients. As male patients with HER2-positive breast cancer are generally managed in a similar manner as female patients, the clinical evidence from Enhertu breast cancer studies can be generalized to male patients.

The data cut-off for the primary analysis occurred when all patients had at least 6 months of follow-up or had discontinued from the study. At the data cut-off, the median study duration (interval between last follow-up visit and first dose) across all doses was 7.8 months (range: 0.7 to 17.2 months).

The primary efficacy endpoint was the confirmed objective response rate (ORR) as assessed by an independent central review (ICR) based on tumor scans in the intent-to-treat population. The objective response rate was defined as the proportion of patients who achieved a best overall response of complete response or partial response, with confirmation of response, based on response evaluation criteria in solid tumours (RECIST) version 1.1. A key secondary endpoint was duration of response.

The results of the study demonstrated that in the 184 patients enrolled to receive Enhertu 5.4 mg/kg once every 3 weeks, the confirmed objective response rate was 60.9% (95% Confidence Interval [CI]: 53.4, 68.0) and the median duration of response was 14.8 months (95% CI: 13.8, 16.9). Progression-free survival and overall survival were also measured in the study; however, the results of these endpoints are difficult to interpret without statistical inference and a comparator treatment.

Supportive Study

Study J101 was a Phase I, two-part (dose escalation followed by dose expansion), multicenter, nonrandomized, open-label, multiple-dose, first-in-human study of Enhertu, with study sites in Japan and the United States. The dose escalation portion (Part 1, 27 patients) was intended to identify the maximum tolerated dose and the recommended dose of Enhertu. The subsequent dose expansion portion (Part 2, 265 patients) was intended to further assess the safety, tolerability, and efficacy of trastuzumab deruxtecan at the two doses selected in Part 1 (5.4 mg/kg and 6.4 mg/kg).

In Study J101, the primary efficacy analysis was performed on the Enrolled Analysis Set (intent-to-treat population), which included all registered patients with metastatic HER2-positive breast cancer who received Enhertu 5.4 mg/kg dose in either the dose escalation part or dose expansion part of the study. When including all tumor types and doses in dose escalation and dose expansion, 292 patients were enrolled in the study. Of these 292 patients, 51 patients with metastatic HER2-positive breast cancer were enrolled and assigned to receive 5.4 mg/kg of Enhertu. Of these patients, 50/51 (98.0%) were female; the median age was 58.0 years (range: 28 to 77), with 34/51 (66.7%) patients <65 years of age and 17/51 (33.3%) patients ≥65. The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 for 33/51 (64.7%) patients and 1 for 17/51 (33.3%) patients; no patients had an ECOG PS of 2 as per protocol. Thirty-two of the 51 (62.7%) patients were hormone receptor (HR)-positive, 31/51 (60.8%) patients were estrogen-receptor positive, and 21/51 (41.2%) patients were progesterone-receptor positive.

Overall, the efficacy results from Study J101 were generally supportive of those of the pivotal study. The confirmed ORR based on ICR was 51.0% (95% CI: 36.6, 65.2), with 26/51 patients with response: 2/51 (3.9%) patients had a confirmed best overall response (BOR) of complete response (CR) and 24/51 (47.1%) patients had a confirmed BOR of partial response (PR).

To facilitate the interpretation of the efficacy results from Studies U201 and J101, the sponsor performed two analyses: 1) an analysis of real-world evidence in a cohort of patients matching the characteristics of patients in Study U201, and 2) a systematic review of published studies in patients with unresectable or metastatic HER2-positive breast cancer who had received one or more prior therapies. The objective response rate was 12.2% in the real-world matching cohort and ranged from 8% to 47% in the studies included in the sponsor’s literature review.

In comparison, Enhertu monotherapy at the recommended dose demonstrated numerically higher objective response rates in Studies U201 and J101, indicating that Enhertu has the potential to provide a significant increase in efficacy. Therefore, the efficacy results, primarily the objective response rate, supported by the evidence of durability are considered promising evidence of effectiveness.

Indication

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

Enhertu (trastuzumab deruxtecan) as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens.

Health Canada recommended that the target population for the indication be modified to patients who have received prior treatment with T-DM1. This description better aligns with the eligibility criteria of the pivotal study and it provides better clarity on the therapeutic place of Enhertu, that is, after treatment with T-DM1. The sponsor accepted the recommendation. Accordingly, Health Canada approved the following indication:

Enhertu (trastuzumab deruxtecan) as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1).

Overall Analysis of Efficacy

Enhertu represents a new treatment option for adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with T-DM1. Based on the evidence reviewed, the benefit/risk profile is considered favourable for Enhertu under the recommended condition of use.

The clinical benefit of Enhertu under the recommended condition of use is to be confirmed based on results of the ongoing Phase III Study U301 which compares Enhertu 5.4 mg/kg three times weekly with an investigator’s choice comparative therapy in a patient population similar to that of Study U201.

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

Clinical Safety

The safety evaluation of Enhertu is based primarily on data from a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu at 5.4 mg/kg in Studies U201 and J101 (described in the Clinical Efficacy section).

The most common adverse reactions (occurring with a frequency ≥20%) were: nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutrophil count decreased, diarrhea, cough, leukopenia, headache and platelet count decreased. Serious adverse reactions occurred in 20% of patients receiving Enhertu. Serious adverse reactions that occurred in >1% of patients who received Enhertu were interstitial lung disease, vomiting, nausea, and hypokalemia. Fatalities due to adverse events occurred in 5.1% of patients, including 2.6% of patients who developed interstitial lung disease (2.6%).

Dose interruptions due to adverse reactions occurred in 25% of patients treated with Enhertu. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia (14.5%), anemia (3.4%), upper respiratory tract infection (3.0%), leukopenia (3.0%), interstitial lung disease (2.6%), thrombocytopenia (2.6%), and fatigue (2.1%). Dose reductions occurred in 15% of patients treated with Enhertu. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue (3.8%), nausea (3.4%), and neutropenia (3.4%). Discontinuation of therapy due to an adverse reaction occurred in 11% of patients treated with Enhertu. The most frequent adverse reaction (>2%) associated with permanent discontinuation was interstitial lung disease (9.4%).

Clinically important abnormal laboratory findings included decreased white blood cell count, anemia, decreased neutrophil count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, and hypokalemia. A total of 37 of 219 (16.9%) patients met the criteria for a Grade 2 left ventricular ejection fraction decrease during the study.

Most adverse reactions and abnormal laboratory changes appeared to be manageable through close monitoring, symptomatic treatment and dose adjustment (i.e., interruption, dose reduction or discontinuation).

As eligible patients in the clinical studies must meet the pre-defined eligibility criteria, the safety of Enhertu has not been evaluated in patients with inadequate organ functions at baseline. Enhertu has not been studied in patients with a history of severe hypersensitivity reactions to previous antibody drugs. Safety has not been adequately studied in patients ≥75 years of age. 

Based on non-clinical studies, Enhertu is embryo-fetal toxic and can cause impairment in male reproductive function and fertility. Enhertu can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Enhertu in pregnant women; however, in post-marketing reports, the use of trastuzumab during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Enhertu can also cause embryo-fetal harm when administered to a pregnant woman. Enhertu should not be administered to pregnant women and patients should be informed of the potential risks to the fetus before they become pregnant.

Enhertu has the potential to harm infants via exposure through breast feeding. There are no data regarding the presence of Enhertu in human milk. As human IgG is excreted in human milk, Enhertu, a humanized IgG1 conjugated to deruxtecan, may be excreted in human milk. Due to the potential for serious adverse reactions in breastfeeding infants, women should discontinue breastfeeding prior to initiating treatment with Enhertu. Women may begin breastfeeding 7 months after concluding treatment.

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

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Enhertu: interstitial lung disease and pneumonitis; embryo-fetal toxicity; and the risk of medication errors between Enhertu (trastuzumab deruxtecan) and trastuzumab or trastuzumab emtansine. Additional warnings are included under Warnings and Precautions and include: left ventricular ejection fraction decrease; driving and operating machinery; neutropenia; and infusion-related reactions.

Overall Analysis of Safety

Overall, the safety profile of Enhertu is considered acceptable in the context of this serious, life-threatening disease. Most adverse reactions and abnormal laboratory changes appear to be manageable through close monitoring, symptomatic treatment, and dose adjustment (i.e., interruption, dose reduction or discontinuation). As part of the marketing authorization, the sponsor has agreed to provide the final clinical study report for the Phase III Study U301 to confirm the clinical benefit of Enhertu.

The safety of Enhertu in patients with poor performance status and/or significant baseline comorbidities was not been adequately evaluated and is a source of uncertainty. Key eligibility criteria, as well as demographics and disease characteristics are adequately described in the Enhertu Product Monograph to inform health professionals of the study population. The Enhertu Product Monograph also indicates the lack of evidence in patients with severe renal impairment or moderate to severe hepatic impairment.

The risks associated with Enhertu will be monitored in the post-market setting. The sponsor has submitted a Risk Management Plan (RMP), which was reviewed by Health Canada. The RMP was revised based on Health Canada’s recommendations to mitigate noted safety concerns and the final version was considered acceptable. In order to mitigate the risk of interstitial lung disease, the sponsor proposed educational material for both health professionals and patients as well as a Patient Alert Card. These additional risk mitigation measures were considered acceptable.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical studies included primary pharmacology, safety pharmacology, non-clinical pharmacokinetic, in vitro drug-drug interaction, and toxicity studies.

In vitro, Enhertu bound to human recombinant HER2 protein but not to recombinant epidermal growth factor receptor (EGFR), HER3, or HER4 proteins. Enhertu inhibited the activity of topoisomerase I, in vitro, as shown by the inhibition of supercoiled deoxyribonucleic acid (DNA) relaxation in a dose-dependent manner. In addition, Enhertu exhibited cell growth inhibitory activity towards HER2-expressing cells and showed antibody-dependent cellular cytotoxic activity.

In vivo, Enhertu showed anti-tumor activity in HER2-positive or HER2-low-expressing breast cancer tumor xenograft mouse models.

In monkeys, the major observed target organs of toxicity following administration of Enhertu included the bone marrow, skin, lung, testis, kidney, and the gastrointestinal system. Except for the findings in the skin and kidneys, all the other histopathological findings were reversible by the end of the recovery period. Enhertu had no effect on the cardiovascular, respiratory, or central nervous systems and had no effect on human Ether-à-go-go-Related Gene (hERG) currents.

Cytochrome P450 (CYP) 3A4 and CYP 3A5 are the primary CYP isoforms involved in the metabolism of Enhertu. Concomitant use of Enhertu with a strong CYP3A4 inducer or inhibitor may influence MAAA-1181a exposure.

The topoisomerase inhibitor component of Enhertu was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay, and was not mutagenic in an in vitro bacterial reverse mutation assay.

Dedicated fertility studies have not been conducted with Enhertu. In monkeys, histological findings in the testis suggest that at doses ≥30 mg/kg (≥9 times the exposure at the human recommended dose of 5.4 mg/kg), Enhertu may impair male reproductive function and fertility. Based on its mechanism of action, a Warning and Precaution for embryo-fetal toxicity was recommended for inclusion in the label. Due to the potential of Enhertu to cause fetal harm, effective contraception use is recommended for female patients during treatment with Enhertu and for at least 7 months following the last dose. Effective contraception use is also recommended for male patients with female partners of reproductive potential during treatment with Enhertu and for at least 4 months following the last dose.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Enhertu Product Monograph. In view of the intended use of Enhertu, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Enhertu Product Monograph to address the identified safety concerns.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Trastuzumab deruxtecan is a HER2 targeted antibody drug conjugate (ADC) composed of three components:

  1. a humanized anti-HER2 IgG1 monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, covalently linked to
  2. a topoisomerase I inhibitor, an exatecan derivative, via
  3. a tetrapeptide based cleavable linker.

Detailed characterization studies were performed to provide assurance that trastuzumab deruxtecan 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 limits.

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

The drug substance antibody intermediate is a monoclonal recombinant and humanized anti-HER2 immunoglobulin G1κ (IgG1κ) antibody with the same amino acid sequence as trastuzumab. It is manufactured using Chinese hamster ovary cells. The manufacturing process consists of a series of stages including cell culture, harvest, purification, viral inactivation, filtration steps, filling, and freezing.

The drug substance drug-linker intermediate is chemically manufactured at three commercial manufacturing sites. The manufacturing process involves coupling the drug substance intermediate and the linker intermediate.

The commercial manufacturing process of trastuzumab deruxtecan drug substance consists of thawing of the antibody intermediate, reduction of the disulfide bridge, conjugation of the drug-linker intermediate, and quenching of the excess drug linker to stop the reaction. The crude solution is then purified by diafiltration and concentrated by ultrafiltration before filling.

To manufacture Enhertu drug product, bulk drug substance is thawed, compounded, sterile filtered, and filled into glass vials. The drug product is then lyophilized, capped, and visually inspected.

Appropriate control strategies have been established to ensure the consistent production of high quality drug-linker intermediate, antibody intermediate, trastuzumab deruxtecan drug substance, and Enhertu drug product. These strategies include in-process controls and parameters, control of raw materials, and specifications for controlling impurities, purity, and bioactivity.

Process validation studies have demonstrated that the manufacturing facilities involved in the production of the drug-linker intermediate, antibody intermediate, trastuzumab deruxtecan drug substance, and the Enhertu drug product, are capable of consistently manufacturing product of suitable quality. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process 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 deruxtecan 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 and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Each lot of Enhertu drug product is tested for identity, quantity, purity, potency, impurities, and safety. Established test specifications and validated analytical test methods are considered acceptable.

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.

Enhertu is a Schedule D (biologic) drug and is, therefore, subject to Health Canada’s Lot Release Program before sale as per Health Canada’s Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 to 8 ºC for Enhertu is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are 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 of the drug substance antibody intermediate was planned, however, due to the Coronavirus disease (COVID-19) pandemic, was not scheduled. In order to mitigate the risk of not performing an OSE, an evaluation of the suitability of the drug substance intermediate manufacturing facility was performed based on documentation. The results of this assessment were satisfactory.

An OSE of the drug substance manufacturing site was not conducted based on the mitigating factor that the drug substance manufacturing process involves simple chemical reaction and purification steps.

Based on a risk assessment score determined by Health Canada, an OSE of the drug product manufacturing facility was not deemed necessary.

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

Adventitious Agents Safety Evaluation

Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. Certification letters attesting to these claims were provided by the sponsor. The excipients used in the drug product formulation are not of animal or human origin.

 

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