Summary Basis of Decision for Kadcyla
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Kadcyla is located below.
Recent Activity for Kadcyla
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 Kadcyla
Updated:
The following table describes post-authorization activity for Kadcyla, a product which contains the medicinal ingredient trastuzumab emtansine. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02412365 - 100 mg/vial trastuzumab emtansine, powder for solution, intravenous administration
- DIN 02473224 - 160 mg/vial trastuzumab emtansine, powder for solution, intravenous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 263309 | 2022-04-11 | Issued NOC 2022-11-09 | Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 264693 | 2022-05-31 | Issued NOC 2022-10-13 | 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 section of the PM. An NOC was issued. |
| SNDS # 253446 | 2021-06-14 | Issued NOC 2021-11-02 | 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 section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. |
| Summary Safety Review | Not applicable | Posted 2021-06-24 | Summary Safety Review posted for Kadcyla (Assessing the potential risk of Tumor Lysis Syndrome). |
| New safety and effectiveness review | Not applicable | Started between 2020-08-01 and 2020-08-31 | Health Canada started a safety and effectiveness review for Kadcyla related to Tumour Lysis Syndrome (quick cancer cells breakdown severely affecting many organs). |
| NC # 237722 | 2020-03-27 | Issued NOL 2020-07-03 | 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 section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 227372 | 2019-05-01 | Issued NOC 2019-11-25 | Submission filed as a Level I – Supplement to for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the adjuvant treatment of HER2-positive early breast cancer patients who have residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published. |
| NC # 226830 | 2019-04-15 | Issued NOL 2019-07-18 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug product manufacturing facility and the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Drug product (DIN 02473224) market notification | Not applicable | Date of first sale: 2018-10-24 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 220881 | 2018-10-10 | Issued NOL 2018-10-15 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the testing procedures for the drug substance and to create a secondary reference standard. The exact same changes were reviewed and approved for Herceptin (trastuzumab). An NOL was issued. |
| SNDS # 212091 | 2017-12-13 | Issued NOC 2018-02-20 |
Submission filed as a Level I - Supplement to update the inner and outer labels and package insert. The submission was reviewed and considered acceptable, and an NOC was issued. An additional DIN (02473224) was issued. |
| NC # 206760 | 2017-06-20 | Issued NOL 2017-08-31 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a scale-up of the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 206152 | 2017-05-31 | Issued NOL 2017-07-12 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 193785 | 2016-03-31 | Issued NOC 2017-03-10 |
Submission filed as a Level I - Supplement to update the PM based on the data from Phase I study BO25499 and to update the PM to reflect revisions in the company core data sheet. As a result of the SNDS, modifications were made to the Warnings and Precautions, Dosage and Administration, and Action and Clinical Pharmacology sections of the PM. Corresponding changes were made to the PM Part III Consumer information. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 200056 | 2016-11-07 | Issued NOC 2017-01-20 |
Submission filed as a Level I - Supplement to change the inner label. The submission was reviewed and considered acceptable, and an NOC was issued. |
| NC # 197773 | 2016-08-19 | Issued NOL 2016-08-29 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance, and stability testing protocol for the drug substance. The exact same changes were reviewed and approved for Herceptin (trastuzumab). An NOL was issued. |
| SNDS # 187575 | 2015-09-09 | Issued NOC 2016-04-26 |
Submission filed as a Level I – Supplement for the approval of an alternate manufacturing site of the drug product. Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC # 189113 | 2015-11-02 | Issued Not Satisfactory Notice 2016-01-15 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to propose safety changes to the Product Monograph. The NC was issued a Not Satisfactory Notice as the changes filed were considered appropriate for a Supplemental New Drug Submission (no addition of risk management measures). |
| SNDS # 186426 | 2015-07-23 | Issued NOC 2016-01-11 | Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the trastuzumab drug substance. There were no changes to the drug product as a result. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC #184050 | 2015-04-27 | Issued No Objection Letter 2015-07-30 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to scale-up the manufacturing process. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC #176991 | 2014-08-06 | Issued No Objection Letter 2014-10-07 |
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to propose safety updates to the Warnings and Precautions and Adverse Reactions sections of the Product Monograph (PM), as well as the PM Part III: Consumer Information. These changes were proposed to be consistent with recently approved PM changes for Herceptin (medicinal ingredient trastuzumab). The submission was reviewed, and as a result additional changes were made to the Warnings and Precautions section and PM Part III. A No Objection Letter was issued. |
| Dear Healthcare Professional Letter posted | Not applicable | Posted 2013-10-09 |
Dear Healthcare Professional Letter posted (Kadcyla [trastuzumab emtansine] and Herceptin [trastuzumab] - Potential Risk for Medication Error Due to Name Confusion), containing important safety information for healthcare professionals. |
| Drug product (DIN 02412365) market notification | Not applicable | Date of first sale: 2013-10-09 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 162414 | 2013-02-08 | Issued NOC 2013-09-11 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Kadcyla
Date SBD issued: 2013-12-03
The following information relates to the new drug submission for Kadcyla.
Trastuzumab emtansine, 20 mg/mL, Powder for solution, Intravenous
Drug Identification Number (DIN):
- 02412365
Hoffmann-La Roche Ltd.
New Drug Submission Control Number: 162414
On September 11, 2013, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product Kadcyla.
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 Kadcyla is favourable as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer who received both prior treatment with Herceptin (trastuzumab) and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy.
1 What was approved?
Kadcyla, an antibody-drug conjugate and an antineoplastic agent, was authorized as a single agent for the treatment of patients with HER2-positive, metastatic breast cancer who received both prior treatment with Herceptin (trastuzumab) and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy. HER2-positive breast cancer is a breast cancer that overexpresses a protein called human epidermal growth factor receptor 2 (HER2) that is associated with aggressive tumour growth.
Kadcyla is contraindicated in patients with a known hypersensitivity to this drug or to any ingredient in the formulation or component of the container. Kadcyla was approved for use under the conditions stated in the Kadcyla Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Kadcyla (100 mg and 160 mg trastuzumab emtansine) is presented as a powder to be reconstituted for intravenous administration. Kadcyla contains the active substance trastuzumab emtansine which is made up of two types of medicine that are linked together: a monoclonal antibody, trastuzumab (Herceptin) and an anti-mitotic agent, DM1 (a derivative of maytansine). In addition to the medicinal ingredient (trastuzumab emtansine), the powder contains polysorbate 20, sodium hydroxide, succinic acid, 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 Kadcyla Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Kadcyla approved?
Health Canada considers that the benefit/risk profile of Kadcyla is favourable as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (MBC) who received both prior treatment with Herceptin (trastuzumab) and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy.
Breast cancer is the most common cause of cancer diagnosed in women. Approximately 20-25% of breast cancers in humans have an amplification or overexpression of HER2. Although first-line treatment options exist for patients with MBC, the disease eventually progresses/recurs, and MBC remains largely incurable. Therefore, there is an unmet medical need for HER2-positive MBC patients who failed frontline therapy.
Kadcyla, as a single agent, has been shown to be efficacious in patients with HER2-positive MBC who failed frontline therapy. The efficacy data of the pivotal study, TDM4370g/BO21977 (EMILIA) demonstrated a statistically significant and clinically relevant improvement in both progression-free survival (PFS) and overall survival (OS) in patients administered with Kadcyla compared with those treated with lapatinib plus capecitabine (control arm). These results were consistent among most subgroups and were also supported by key secondary endpoints.
Based on the pivotal study EMILIA, the most common adverse events (AEs) (≥20%) occurring at a higher incidence (≥2%) in the Kadcyla arm compared with the control arm were thrombocytopenia, hemorrhage, constipation, fatigue, increased aspartate transaminase (AST)/alanine transaminase (ALT), musculoskeletal pain, arthralgia, headache, peripheral neuropathy and epistaxis. A total of 44.5% of patients in the Kadcyla arm and 59.6% in the control arm developed Grade ≥3 AEs.
The incidence of serious adverse events (SAEs) in the Kadcyla arm (17.6%) was less than that of the control arm (19.5%), but infections [4.7% versus (vs.) 3.1%], general disorders (2.9% vs. 1.8%), musculoskeletal and connective tissue disorders (1.4% vs. 0.2%) and hepatobiliary disorders (0.8% vs. 0.2%) were reported at a higher incidence in the Kadcyla arm compared with the control arm. Gastrointestinal disorders (6.1% vs 3.3%), Metabolism and Nutrition Disorders (0.8% vs 0.6%), Respiratory, Thoracic and Mediastinal Disorders (3.3% vs 1.0%), Skin and Subcutaneous Tissue Disorders (0.6% vs 0.4%), and Vascular Disorders (1.0% vs 0.2%) were reported at a higher incidence in the control arm vs the Kadcyla arm.
The following serious safety concerns were identified in this submission and were listed in the Serious Warnings and Precautions Box of the Kadcyla Product Monograph: a risk of medication errors between Kadcyla (trastuzumab emtansine) and Herceptin (trastuzumab); liver toxicity; cardiotoxicity; and embryo-fetal toxicity. Other important AEs associated with Kadcyla included thrombocytopenia, hemorrhage, peripheral neuropathy and pneumonitis.
A Risk Management Plan (RMP) for Kadcyla was submitted by Hoffmann-La Roche Limited 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.
Based on the review of data on clinical efficacy and safety, the therapeutic benefits of Kadcyla are considered to outweigh the potential risks. Kadcyla has an acceptable safety profile based on the non-clinical data and clinical studies. The risk mitigation and prevention measures for the identified safety issues are managed through labelling and pharmacovigilance. Appropriate warnings and precautions are in place in the Kadcyla Product Monograph to address the identified safety concerns. The overall risk-benefit profile of Kadcyla is considered to be favourable for HER2-positive patients who received both prior treatment with Herceptin (trastuzumab) and taxane-based therapies.
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 Kadcyla?
The drug submission for Kadcyla was reviewed under the Priority Review Policy. Kadcyla demonstrated a significant increase in efficacy with an improved benefit/risk profile compared to existing therapies for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who failed frontline therapy, a condition that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Kadcyla
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2012-11-13 |
| Request for priority status | |
| Filed: | 2012-11-15 |
| Approval issued by the Bureau of Biotherapeutics & Radiopharmaceuticals/Centre for Radiopharmaceuticals and Biotechnology: | 2012-12-13 |
| Submission filed: | 2013-02-08 |
| Screening | |
| Screening Acceptance Letter issued: | 2013-03-15 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2013-09-11 |
| Quality Evaluation complete: | 2013-09-11 |
| Clinical Evaluation complete: | 2013-09-11 |
| Biostatistics Evaluation complete: | 2013-09-11 |
| Labelling Review complete: | 2013-09-11 |
| Notice of Compliance issued by Director General: | 2013-09-01 |
The Canadian regulatory decision on the clinical review of Kadcyla was based on a critical assessment of the Canadian data package. Foreign reviews completed by the United States Food and Drugs Administration (FDA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
In addition to the requirements outlines in the Food and Drugs Act and Regulations, the sponsor has agreed to undertake the commitments listed below:
- The sponsor will submit, the updated safety data at the final overall survival (OS) for the pivotal study EMILIA as per Health Canada's Post-NOC Guidance: Safety and Efficacy. Additionally, if the results obtained in the final OS are different from that of the secondary analysis, then the final data would be submitted to Health Canada.
- The sponsor commits to submitting a labeling only supplement for Herceptin (trastuzumab) in order to update the Herceptin Product Monograph (PM) and Risk Management Plan (RMP) with cross reference to the approved Kadcyla NDS.
- The sponsor commits to submitting results from ongoing clinical trials as per Health Canada's Post-NOC Guidance: Safety and Efficacy.
- The sponsor will submit Periodic Benefit Risk Evaluation Reports (PBRER) for Kadcyla. The sponsor will also submit copies of the yearly interim reports on the cumulative findings and analyses from the Pregnancy Registry in the United States.
- If available, the sponsor will submit to the Biologics and Genetic Therapies Directorate (BGTD), the results from future clinical trials with Kadcyla to confirm the treatment benefit of Kadcyla reported in the post-hoc subgroup analyses for visceral/non-visceral disease status in the pivotal trial (EMILIA).
- The sponsor will develop an appropriate assay for the detection of neutralizing antibodies to Kadcyla. Upon completion of assessment of the neutralizing activity of anti-Kadcyla antibodies in the pivotal study (EMILIA) any available results will be submitted to Health Canada.
- The sponsor will submit to Health Canada the revised training materials for health care providers.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Kadcyla is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate which contains the humanized anti-HER2 immunoglobulin G1 (trastuzumab), covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC [4-(N-maleimidomethyl) cyclohexane-1-carboxylate]. Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules is conjugated to each molecule of trastuzumab.
Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumor cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).
The clinical pharmacology studies characterized the absorption, distribution, metabolism and excretion of Kadcyla. The data from the submitted clinical pharmacokinetic studies are considered sufficient and there are no major concerns to prevent the market authorization of Kadcyla for the specified indication.
A Phase II, open-label electrocardiogram (ECG) study was conducted to evaluate the QTc prolongation liability of Kadcyla in patients with HER2-positive, unresectable locally advanced or metastatic breast cancer (MBC), and to evaluate the safety and tolerability of combined Kadcyla and pertuzumab in patients with early disease progression while receiving Kadcyla alone. This study had important limitations as a source of ECG data that constrain the ability to interpret the data [for example (e.g.) lack of a placebo or active control group]. At the time of maximal plasma concentration [that is (i.e.) 15 minutes post-infusion], no significant increase in the QTcF interval was observed on Cycle 1/Day 1, with a mean change from baseline of 1.10 ms [90% confidence interval (CI) - 1.00, 3.19], whereas, on Cycle 3/Day 1, a significant mean increase from baseline of 4.32 ms (90% CI 1.72, 6.92) was observed. In the absence of a placebo control, the data cannot be adjusted for changes unrelated to drug treatment. The ECG data were collected at the same time as the blood samples for pharmacokinetic determinations. A concentration-response analysis demonstrated positive and statistically significant relationships between change from baseline in QTcF and plasma concentrations of Kadcyla, total trastuzumab (sum of conjugated and unconjugated trastuzumab), and DM1, but the predicted magnitude of the change at mean concentration maximum (Cmax) did not suggest that the extent of QTc prolongation would reach the threshold of regulatory concern at therapeutic doses. Appropriate warnings and precautions are in place in the approved Kadcyla Product Monograph.
No drug-drug interaction studies with Kadcyla (trastuzumab emtansine) in humans have been conducted. In vitro metabolism studies suggest that the anti-mitotic agent, DM1, is metabolized by CYP3A. DM1 does not induce or inhibit P450-mediated metabolism in vitro. Caution should be taken when Kadcyla is co-administered with potent CYP3A inhibitors.
For further details, please refer to the Kadcyla Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Kadcyla was primarily based on one pivotal Phase III study (TDM4370g/BO21977; also referred to as EMILIA). The efficacy was also evaluated in three supportive Phase II studies (TDM4450g, TDM4374g, TDM4258g).
The pivotal Phase III study was a randomized, multicentre, international, open-label clinical study designed to compare the efficacy and safety of Kadcyla vs. the use of lapatinib plus capecitabine (control arm) in patients with HER2-positive unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (MBC) who had received prior taxane and trastuzumab-based therapy, including patients who received prior therapy with trastuzumab and a taxane in the adjuvant setting and who relapsed during or within six months of completing adjuvant therapy. Prior to enrollment, breast tumour samples were required to be centrally confirmed for HER2-positive disease defined as a score of 3+ by immunohistochemistry (IHC) or gene amplification by in situ hybridization (ISH). A total of 991 patients were randomized (1:1) to Kadcyla or lapatinib plus capecitabine. Patients in the Kadcyla arm [number of patients (n) = 495] received 3.6 mg/kg of Kadcyla intravenously (IV) over 30-90 minutes on Day 1 of a 21-day cycle while patients in the control arm (n = 496) received 1,250 mg of lapatinib orally once per day of a 21-day cycle and 1,000 mg/m2 of capecitabine orally twice daily on Days 1-14 of a 21-day cycle. Patients received Kadcyla or lapatinib plus capecitabine until progression of disease (as assessed by the investigator), withdrawal of consent, or unmanageable toxicity.
The co-primary endpoints for this pivotal study were progression-free survival (PFS) assessed by an independent review committee (IRC) and overall survival (OS). The PFS was defined as the time from randomization to documented IRC-assessed progressive disease (PD) or death from any cause (whichever occurred earlier). The OS was defined as the time from the date of randomization to the date of death from any cause. The key secondary endpoints were PFS per investigator, objective response rate (ORR) per IRC, duration of objective response (DOR) and the time to symptom progression.
Patients treated with Kadcyla resulted in a statistically significant improvement in PFS per IRC [hazard ratio (HR): 0.650, 95% CI: 0.549, 0.771; p<0.0001] with an increase in median PFS of 3.2 months compared with patients who received lapatinib plus capecitabine (median PFS of 9.6 months in the Kadcyla arm vs. 6.4 months in the control arm). These results were consistent with the investigator-assessed PFS and among most subgroups.
At the first OS interim analysis, a trend toward an OS benefit was observed in favour of the Kadcyla arm, but did not cross the pre-defined stopping boundary of alpha level. However, a second interim analysis was conducted, and a 32% reduction in the risk of death was observed in the Kadcyla arm compared with the control arm (HR 0.682, 95% CI 0.548, 0.849, p = 0.0006). The p-value met the O'Brien Fleming stopping boundary of the Lan Demets alpha spending function for the second OS interim analysis (p = 0.0037), and therefore reached statistical significance. A clinically meaningful OS improvement of 5.8 months in the Kadcyla arm compared with the control arm was observed (median OS of 30.9 months in the Kadcyla arm vs. 25.1 months in the control arm). This pivotal study met both its co-primary endpoints of PFS per IRC and OS. However, based on both PFS and OS subgroup analyses, the treatment benefit was not clearly demonstrated in patients with non-visceral disease and non-measurable disease based upon investigator assignment at time of randomization. When post hoc analysis of visceral and non-visceral disease was conducted utilizing classifications of disease site based upon published reports, the PFS HRs were 0.69 (95% CI: 0.51, 0.95) and 0.64 (95% CI: 0.53, 0.78) for the non-visceral and visceral subgroups, respectively. The HRs for OS were 0.59 (95% CI: 0.37, 0.94) and 0.73 (95% CI: 0.57, 0.94), respectively. Additionally, the subgroup analysis for patients ≥65 years of age did not demonstrate clear PFS (HR 1.06 (95% CI 0.68, 1.66) or OS (HR 1.05 (95% CI: 0.69, 1.61) advantage.
A higher proportion of patients in the Kadcyla arm [43.6% (173/397)] achieved an ORR per IRC compared to those in the control arm [ORR per IRC of 30.8% (120/389)]. Responders had a median DOR of 12.6 months in the Kadcyla arm whereas those in the control arm had a median DOR of 6.5 months. However, these results should be interpreted cautiously as they were based on responder analyses which are known to bear inherent limitations.
Supportive Studies
The efficacy of Kadcyla were assessed in three supportive phase II studies with HER2-positive MBC patients: TDM4374g (n = 110) and TDM4258g (n = 112), both studies were single-arm, open-label studies in second/third line therapy, and TDM4450g/BO21976 (n = 137), a two-arm, open-label study comparing TDM1 with trastuzumab and docetaxel in first-line therapy.
Single-agent anti-cancer activity of Kadcyla based on the ORR was confirmed in previously treated HER2-positive MBC patients in studies TDM4374g (ORR = 32.7%) and TDM4258g (ORR = 26.9%). In the randomized, controlled, Phase II study with previously untreated patients (TDM4450g/BO21976), the ORRs were 64.2% in the Kadcyla arm compared to 58.0% in the control arm (trastuzumab+docetaxel). Improvement in median PFS with Kadcyla treatment compared to the control arm was also observed (14.2 months and 9.2 months, respectively). There was no difference in overall OS benefit between the two arms, and the median OS was not reached in both arms. Given that the supportive studies were exploratory single-arm studies and/or were conducted in different line of treatment than the pivotal study (EMILIA), and given the relatively small sample size of each study, these efficacy results are not considered to confirmatively support the proposed indication.
The original indication proposed by the sponsor in the New Drug Submission (NDS) was as follows: Trastuzumab emtansine, as a single agent, is indicated for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane.
Following review of the submission, Health Canada revised the indication to: Kadcyla (trastuzumab emtansine), as a single-agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who received both prior treatment with Herceptin (trastuzumab) and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy.
For more information, refer to the Kadcyla Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety evaluation was based primarily on data from the one pivotal study (EMILIA) and three supportive studies (TDM4374g, TDM4258g and TDM4450g/BO21976) previously described in the Clinical Efficacy section. The safety was also assessed in a follow-up open-label extension study (TDM4529g/BO25430), which included 43 patients originally treated with Kadcyla in the Phase I or Phase II studies.
In the pivotal study, the most common adverse events (AEs) (≥20%) occurring at a higher incidence (≥2%) in the Kadcyla arm compared with the control arm were thrombocytopenia, hemorrhage, constipation, fatigue, increased levels of aspartate transaminase (AST)/alanine transaminase (ALT), musculoskeletal pain, arthralgia, headache, peripheral neuropathy and epistaxis. A total of 44.5% of patients in the Kadcyla arm and 59.6% in the control arm developed Grade ≥3 AEs. The incidences of Grade ≥3 thrombocytopenia, anemia, AST/ALT increased and peripheral neuropathy were higher (≥2%) in the Kadcyla arm than in the control arm. The rate of Grade ≥3 thrombocytopenia reported in the Kadcyla arm was higher in Asian patients [40/490 patients (8.2%)] compared to that of the control arm [1/488 patients (0.2%)]. The overall frequency of bleeding events was observed at 33.3% in the Kadcyla arm compared to 16.6% in the control arm. The majority of bleeding events were epistaxis (23.1% of patients) and most were of low-grade intensity. Of the haemorrhage events, 2.0% in the Kadcyla arm vs. 0.8% arm were of Grade ≥3 severity. The causal relationship between severe thrombocytopenia and severe bleeding events was not established. The incidence of serious AEs (SAEs) in the Kadcyla arm (17.6%) was less than that of the control arm (19.5%), but infections (4.7% vs. 3.1%), general disorders (2.9% vs. 1.8%), musculoskeletal and connective tissue disorders (1.4% vs. 0.2%) and hepatobiliary disorders (0.8% vs. 0.2%) were reported at a higher incidence in the Kadcyla arm compared with the control arm. In addition, 21 patients (4.3%) in the Kadcyla arm experienced infusion-related reactions/hypersensitivity which are AEs that were all of Grade ≤2 in severity. Vision disorders occurred more frequently in the Kadcyla arm (7.3%) than in the control arm (2.3%), but they were all of Grade ≤2 in severity. Thirty-five patients (7.1%) discontinued treatment with Kadcyla due to an AE compared with the control arm (8.8% and 11.1% of patients discontinued lapatinib and capecitabine, respectively).
In the pivotal study, a total of 10 patients died (5 in each arm) due to a reason other than progressive disease. In the Kadcyla arm, four of the five patients had neutropenic sepsis/infection, pneumonia or metabolic encephalopathy, and died between 21-35 days after the last dose of Kadcyla. Additionally, two cases of nodular regenerative hyperplasia of the liver were identified from liver biopsies.
The most important all-grade AEs associated with Kadcyla included hepatotoxicity (32.4% in the Kadcyla arm vs. 26.2% in the control arm), thrombocytopenia (31.6% in the Kadcyla arm vs. 3.2% in the control arm), hemorrhage (33.3% in the Kadcyla arm vs. 16.6% in the control arm), peripheral neuropathy (25.9% in the Kadcyla arm vs. 18.9% in the control arm) and pneumonitis (1.6% in the Kadcyla arm vs. 0.8% in the control arm). Infections other than pneumonitis were also reported in the Kadcyla arm such as gastrointestinal infections and urinary tract infections. The incidence of cardiotoxicity appears to be similar between the 2 treatment arms, 2.0% in the Kadcyla arm and 3.3% in the control arm. In addition, Herceptin (trastuzumab), the antibody component of Kadcyla, is known to cause cardiotoxicity, therefore cardiotoxicity may represent a safety concern associated with Kadcyla. Appropriate warnings and precautions regarding liver toxicity and cardiotoxicity are stated in a Serious Warning and Precautions box in the approved Kadcyla Product Monograph to address the identified safety concerns.
Additional safety warnings stated in the Serious Warning and Precautions box include embryo-fetal toxicity and the risk of medication errors between Kadcyla and Herceptin . Kadcyla may cause fetal harm or death when administered to a pregnant woman. The mechanism of action of DM1, the microtubule inhibiting cytotoxic drug component of Kadcyla, suggest that DM1 can cause teratogenicity and embryotoxicity. Also, medication errors can occur between Kadcyla (trastuzumab emtansine) and Herceptin (trastuzumab) mainly due to the similarity in their non-proprietary name and differences in their dosing and treatment schedules [Kadcyla: 3.6 mg/kg every three weeks (q3w); Herceptin: 6-8 mg/kg q3w or 2-4 mg/kg every week (q1w)]. Therefore, risk mitigation strategies were recommended to reduce the potential risk of medication errors between Kadcyla and Herceptin, including labelling (i.e. warning statements in the PM), Dear Health Care Professional Letter (DHCPL) and training materials for health care providers.
The safety profiles of Kadcyla observed in the four supportive studies were generally consistent with that observed in the pivotal study. A total of 3 fatal cases of hepatotoxicity events and two fatal cases of respiratory failure were reported. One Grade 4 acute leukemia and one Grade 4 Stevens-Johnson Syndrome were also observed in studies TDM4258g and TDM4529g/BO25430, respectively. The causal relationship between acute leukemia and Stevens-Johnson Syndrome was not established.
Appropriate warnings and precautions are in place in the approved Kadcyla Product Monograph to address the identified safety concerns.
For more information, refer to the Kadcyla Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of Kadcyla for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who had received prior taxane and trastuzumab-based therapy.
Kadcyla is an HER2-targeted antibody-drug conjugate comprised of an antibody (trastuzumab) covalently linked to the microtubule-inhibitory drug DM1 (a derivative of maytansine) via the stable thioether linker MCC. Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-ovedrexpressing tumor cells, thereby increasing intracellular delivery of DM1 directly to malignant cells.
Based on the results from the non-clinical studies, Kadcyla (trastuzumab emtansine) was more effective than Herceptin (trastuzumab) for its anti-tumour activities using both in vitro cell culture and in vivo xenograft mouse models probably because of the additional cytotoxic effect from DM1.
Kadcyla caused dose-dependent toxicity in monkeys and rats. The toxicities included chepatic and hematologic toxicities, signs of neurologic damage, and increased cellular mitotic arrest. Most of these toxicities were reversible and well tolerated when the dose was at or below 10 mg/kg which was the suggested highest non-severely toxic dose for monkeys after multiple doses.
In monkeys, a single 30 mg/kg dose of Kadcyla given intravenously resulted in moderately increased blood pressure (both systolic blood pressure and diastolic blood pressure). These changes were most consistently observed on Day 5 post dose, but were variable in onset and duration in individual monkeys. However, considering that these effects were only observed in monkeys at 30 mg/kg, which resulted in plasma exposures of Kadcyla about seven times the clinical exposure observed in patients following 3.6 mg/kg Kadcyla administration (based on area under the curve), that increases in blood pressure were found only in 6% of the patient population, and the increase was considered mild (mostly Grade 1 and 2), Health Canada considers the non-clinical results to be acceptable even though possible cardiac toxicity cannot be excluded.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Kadcyla Product Monograph. There are no major pharmacological/toxicological concerns within this submission which preclude authorization of Kadcyla for the treatment of patients with HER2-positive, unresectable LABC or MBC cancer who have received prior treatment with trastuzumab and a taxane. Appropriate warnings and precautionary measures are in place in the Kadcyla Product Monograph to address the identified safety concerns.
For more information, refer to the Kadcyla Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Kadcyla has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.
Characterization of the Drug Substance
Trastuzumab emtansine, the active ingredient in Kadcyla, is a HER2-targeted antibody-drug conjugate comprising 3 components:
- Trastuzumab - a humanized immunoglobulin G1 against the extracellular domain of p185, HER2.
- DM1 - a sulf-hydryl group-containing analogue of the cytotoxic drug maytansine, which binds to tubulin thereby inhibiting microtubule assembly and inducing microtubule disassembly, and causing cell cycle block, mitotic arrest, and apoptosis.
- MCC - a water-soluble, heterobifunctional crosslinker that covalently joins trastuzumab and DM1.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Trastuzumab emtansine is produced in a seven-step manufacturing process using three key intermediates: trastuzumab drug substance (approved for the manufacture of Herceptin), DM1 and SMCC.
The first intermediate, trastuzumab, is the active ingredient in Herceptin, which was approved in Canada on August 13, 1999 for the treatment of patients with metastatic breast cancer whose tumours substantially overexpress the protein HER2. Trastuzumab is supplied as frozen solution containing the active ingredient at 25 mg/mL, formulated in L-histidine buffer with α,α-trehalose dehydrate, and polysorbate 20. The sponsor referenced quality information provided in the original new drug submission and subsequent amendments. Therefore, further review of trastuzumab drug substance was not performed.
The second intermediate, DM1 is maytansinoid, a thiol-containing structural analog of maytansine. The DM1 is manufactured by two manufacturers, whose manufacturing processes are based on the same original DM1 manufacturing process. The DM1 from both manufacturers is released against the same acceptance criteria using comparable and validated analytical methods. Analytical comparability of DM1 produced by both manufacturers and of Kadcyla manufactured from both sources of DM1 has been demonstrated. Extended characterization studies showed that the trastuzumab emtansine from both sources is comparable based on its physicochemical, immunochemical, and biological properties.
The third intermediate, SMCC is a non-cleavable, membrane permeable, heterobifunctional crosslinker that contains N-hydroxysuccinimide (NHS) ester and maleimide groups that allow covalent conjugation of amine-and sulfhydryl-containing molecules. Batch analysis data for SMCC demonstrated that the manufacturing process operates in a consistent manner, yielding product of acceptable quality. The proposed release specification testing using validated analytical methods and justified acceptance criteria are sufficient to ensure acceptable product quality.
The manufacturing process for the drug substance, trastuzumab emtasine includes a sequence of modification and conjugation reactions and associated ultrafiltration steps. The impurity levels appear to be adequately controlled through rigorous monitoring of starting materials, validated clearance by selected manufaturing steps, and established in-process and release specification testing using validated analytical methods and justified acceptance criteria. The final conditioning and fill steps yield formulated bulk that is suitable for long-term storage and is ready to fill without additional processing.
The manufacturing process for the drug product, Kadcyla, comprises a set of unit operations whereby frozen trastuzumab emtansine drug substance is thawed, sterilized by filtration, aseptically dispensed into depyrogenated glass vials, and lyophilized. The closed vials are sealed with aluminum caps, and subjected to 100% visual inspection. The manufacturing process is subject to a set of established operating conditions, and performance monitoring using in-process testing by validated or qualified compendial analytical methods against justified acceptance criteria.
The manufacturing process was subjected to a comprehensive set of validation and characterization studies which confirmed the effectiveness and robustness of individual unit operations operated using nominal conditions and at the extremes of acceptable operating ranges, and to establish its overall consistency.
Control of the Drug Substance and Drug Product
Process validation and batch analysis data for the drug substance, demonstrate that the manufacturing process operates in a consistent manner, yielding product of acceptable quality. The product generated at various stages of manufacturing process development was demonstrated to be of comparable quality, supporting the linkage between studies conducted at various stages of clinical development.
The quality of the drug product, Kadcyla, is assessed against release specification, which incorporates tests to assess relevant characteristics of the dosage form and reconstituted active ingredient, excipient composition, and conformance with compendial requirements. The associated analytical methods were validated or qualified, and the acceptance criteria were appropriately justified.
Three consecutively manufactured drug product lots were provided for consistency testing of purity and potency. The test results met the established release specification and were deemed to be in agreement (within the variability of the analytical method) with the provided certificate of analysis, and therefore are considered acceptable. Potency testing was performed. The test results met the established release specification, and therefore are considered acceptable.
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 36 months shelf-life at 2 to 8°C for Kadcyla drug product is considered acceptable.
The proposed packaging and components are considered acceptable.
The results of appropriate stability studies were used to demonstrate compatibility of the lyophilisate with the primary packaging, and the appropriateness of established storage conditions throughout the proposed shelf-life. Furthermore, in-use stability was demonstrated, considering the compatibility of reconstituted and diluted Kadcyla with infusion devices and exposure to environmental conditions associated with routine dose administration.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment are considered suitable for the manufacture of trastuzumab emtansine drug substance and Kadcyla drug product.
An On-Site Evaluation (OSE) of the drug substance and drug product manufacturing facilities were not performed as part of the current application due to the short review time (priority review), lack of issues identified during the review, and the relative simplicity of the production processes.
Adventitious Agents Safety Evaluation
The trastuzumab emtansine manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.
Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately controlled through validated clearance and testing to ensure freedom from adventitious agents. The excipients used in the Kadcyla product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| KADCYLA | 02412365 | HOFFMANN-LA ROCHE LIMITED | TRASTUZUMAB EMTANSINE 100 MG / VIAL |
| KADCYLA | 02473224 | HOFFMANN-LA ROCHE LIMITED | TRASTUZUMAB EMTANSINE 160 MG / VIAL |