Summary Basis of Decision for Tukysa
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 Tukysa is located below.
Recent Activity for Tukysa
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 Tukysa
Updated:
The following table describes post-authorization activity for Tukysa, a product which contains the medicinal ingredient tucatinib. 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 and Applications Guidance.
Drug Identification Number (DIN):
DIN 02499835 – 150 mg tucatinib, tablet, oral administration
DIN 02499827 – 50 mg tucatinib, tablet, oral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DINs 02499835 and 02499827) market notification | Not applicable | Date of first sale:2022-09-23 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 252823 | 2021-05-18 | 2021-07-09 | Submission filed to change the name of the drug sponsor from Seattle Genetics, Inc. to Seagen Inc. |
| Drug product (DIN 02499827) market notification | Not applicable | Date of first sale:2020-10-08 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| Drug product (DIN 02499835) market notification | Not applicable | Date of first sale:2020-08-27 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 235295 | 2020-01-20 | Issued NOC2020-06-05 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Tukysa
Date SBD issued: 2020-10-01
The following information relates to the new drug submission for Tukysa.
Tucatinib
Drug Identification Number (DIN):
- DIN 02499835 - 150 mg tucatinib, tablet, oral administration
- DIN 02499827 - 50 mg tucatinib, tablet, oral administration
Seattle Genetics Inc.
New Drug Submission Control Number: 235295
On June 5, 2020, Health Canada issued a Notice of Compliance to Seattle Genetics Inc. for the drug product, Tukysa.
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-harm-uncertainty profile of Tukysa in combination with trastuzumab and capecitabine is favourable for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine, separately or in combination.
Clinical trial data supporting the effectiveness of Tukysa in combination with trastuzumab and capecitabine are limited to patients who had received at least one prior HER2-directed therapy in the metastatic setting.
1 What was approved?
Tukysa, a protein kinase inhibitor, was authorized in combination with trastuzumab and capecitabine for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine, separately or in combination.
Clinical trial data supporting the effectiveness of Tukysa in combination with trastuzumab and capecitabine are limited to patients who had received at least one prior HER2-directed therapy in the metastatic setting.
No data are available to Health Canada regarding the use of Tukysa in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.
Caution should be used when treating geriatric patients (65 years of age and older) with Tukysa as an increased incidence of serious adverse events and treatment discontinuation has been observed in this patient population relative to younger patients.
Tukysa 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.
Tukysa 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.
Tukysa (50 mg and 150 mg tucatinib) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains colloidal silicon dioxide, copovidone, crospovidone, potassium chloride, sodium bicarbonate, sodium chloride, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, and yellow iron oxide non-irradiated.
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 Tukysa Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Tukysa approved?
Health Canada considers that the benefit-harm-uncertainty profile of Tukysa in combination with trastuzumab and capecitabine is favourable for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), separately or in combination.
Clinical trial data supporting the effectiveness of Tukysa in combination with trastuzumab and capecitabine are limited to patients who had received at least one prior HER2-directed therapy in the metastatic setting.
In Canada, breast cancer is the most common cancer in women and the third most common cancer overall. Accounting for 15% to 30% of breast cancers, HER2-positive breast cancer is a serious and life-threatening disease that disproportionately affects younger patients and tends to be more aggressive and more likely to recur than HER2-negative breast cancer. Once HER2-positive breast cancer has metastasized, the estimated 5-year overall survival rate ranges from 15% to 26%. Further, breast cancer patients with brain metastases have a poorer prognosis relative to those without brain metastases. Approximately 1% of breast cancer cases occur in men.
Human epidermal growth factor receptor 2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. In cancer cells, HER2 protein levels can be increased 10- to 100-fold above levels found in normal cells.
First-line treatment for most patients with HER2-positive metastatic breast cancer is a combination of trastuzumab plus pertuzumab and a taxane, unless the patient has a contraindication to taxanes. Within 2 years, the majority of patients treated with this combination will progress. If the disease progressed during or after first-line HER2-targeted therapy, T-DM1 is recommended as second-line treatment. If a patient's HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment, and the patient has already received pertuzumab and T-DM1, a third-line or greater HER2-targeted therapy-based treatment is recommended. Options include lapatinib plus capecitabine, as well as other combinations of chemotherapy, lapatinib and trastuzumab, or hormonal therapy (in patients with estrogen receptor-positive and/or progesterone receptor-positive disease). However, the efficacy of these regimens in this setting remains modest, with reported median progression-free survival (PFS) of 3.3 to 4.9 months and median overall survival (OS) of 15.8 to 17.2 months. Therefore, at the time of authorization, there was a significant unmet medical need for HER2-positive metastatic breast cancer patients who have progressed despite receiving the current standard of care.
Tukysa (tucatinib) is an orally administered, reversible HER2-targeted small molecule tyrosine kinase inhibitor. In vitro, tucatinib inhibits phosphorylation of HER2 and human epidermal growth factor 3 (HER3), resulting in inhibition of downstream cell signaling and cell proliferation, and induces death in HER2 driven tumour cells.
The market authorization of Tukysa in combination with trastuzumab and capecitabine for its approved indication was based primarily on efficacy and safety data provided by a randomized, double-blind, placebo-controlled study known as HER2CLIMB. Enrolled patients (number of patients [n] = 612, including five men) were required to have HER2-positive unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and to have had prior treatment with trastuzumab, pertuzumab, and T-DM1, separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. All patients had received at least one prior HER2-directed agent in the metastatic setting. Overexpression or amplification of HER2 was confirmed by central laboratory analysis prior to patient enrollment.
Patients with brain metastases, including those with untreated or progressing lesions, were eligible to enroll provided they were neurologically stable and did not require immediate radiation or surgery. Patients who received systemic corticosteroids for control of symptoms of central nervous system metastases <28 days prior to the first dose of study treatment were excluded from the trial. The trial also excluded patients with leptomeningeal disease.
The primary efficacy endpoint was PFS in the first 480 randomized patients, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Secondary efficacy endpoints were evaluated in all 612 randomized patients and included OS, PFS among patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).
The median duration of exposure to Tukysa was 7.3 months (range: <0.1, 35.1) for patients in the Tukysa treatment arm compared to 4.4 months (range: <0.1, 24.0) for patients in the placebo treatment arm. After a median duration of follow-up of 10.4 months, there was a statistically and clinically significant reduction (46%) in the risk of a PFS event in patients treated with Tukysa compared to patients in the placebo treatment arm. This corresponded to an increase in the median PFS from 5.6 months in the placebo treatment arm to 7.8 months in the Tukysa treatment arm.
Secondary efficacy endpoints also statistically significantly favoured the Tukysa treatment arm, with median OS increasing from 17.4 months for the placebo treatment arm to 21.9 months for the Tukysa treatment arm. Patients with brain metastases at baseline had a median PFS of 7.6 months in the Tukysa treatment arm compared to 5.4 months in the placebo treatment arm. Additionally, confirmed ORR by BICR in patients with measurable disease was 40.6% for the Tukysa treatment arm compared to 22.8% for the placebo treatment arm. Efficacy results were consistent across all patient subgroups including hormone receptor status, presence or history of brain metastases, Eastern Cooperative Oncology Group performance status (0 vs. 1), and region (Canada, the United States, or the rest of the world).
Nearly all patients enrolled in HER2CLIMB experienced a treatment-emergent adverse event (TEAE), and the overall incidence of TEAEs was similar between the Tukysa and the placebo treatment arms (99% vs. 97%). The most common TEAEs in the Tukysa treatment arm (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Adverse events (AEs) were measured from least severe (Grade 1) to most severe (Grade 5). Grade ≥3 AEs occurred in 53% of Tukysa-treated patients, compared to 45.7% in the placebo treatment arm; most commonly palmar-plantar erythrodysesthesia, diarrhea, hepatotoxicity, increased alanine aminotransaminase (ALT), and fatigue. Treatment-related adverse events occurred in 85% of those in the Tukysa treatment arm compared to 73% of those in the placebo treatment arm. Serious adverse events were balanced between the two treatment arms (26% vs. 27%), with the most common in the Tukysa treatment arm being diarrhea (4%), vomiting (2%), nausea (2%), abdominal pain (2%), and seizure (2%).
Important safety signals for Tukysa include severe diarrhea and severe hepatotoxicity. Adverse events leading to treatment discontinuation of Tukysa or placebo occurred in 6% of patients in the Tukysa treatment arm compared to 3% of patients in the placebo treatment arm. The most common adverse events leading to treatment discontinuation of Tukysa were diarrhea (1%) and increased ALT (1%). Adverse events leading to dose reduction occurred in 21% of patients in the Tukysa treatment arm compared to 11% of patients in the placebo treatment arm. The most common adverse events leading to dose reduction of Tukysa were diarrhea (6%), increased ALT (5%), and increased aspartate aminotransferase (4%).
The safety profile of Tukysa is considered acceptable, in the context of this severe, life-threatening disease, with adverse events typically manageable through the use of Tukysa dose reduction, temporary treatment discontinuation, and/or standard medical care. Appropriate labelling is included in the Tukysa Product Monograph, including recommendations regarding adverse event monitoring and dose modifications, to adequately manage the risks associated with Tukysa therapy. In addition, the following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Tukysa:
- Tukysa in combination with trastuzumab and capecitabine can cause severe diarrhea, leading to dehydration, acute kidney injury and death. Antidiarrheal treatment may be indicated.
- Tukysa can cause severe hepatotoxicity; monitor transaminase and bilirubin.
- Tukysa may cause fetal harm and developmental malformation when administered to a pregnant woman.
A Risk Management Plan (RMP) for Tukysa was submitted by Seattle Genetics 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 for Tukysa was considered to be acceptable. The Sponsor will be requested to:
- submit biennial Periodic Safety Update Reports/Periodic Benefit-Risk Evaluation Reports (PSURs/PBRERs) for the first 4 years following marketing in Canada;
- include in the upcoming PSURs/PBRERs information specific to the summary of the safety data obtained from all pharmacovigilance activities (interim and final reports), and the ongoing/planned studies, including HER2CLIMB-02, an ongoing/planned randomized, double-blind, Phase 3 study of tucatinib or placebo in combination with T-DM1 for patients with unresectable locally-advanced or metastatic HER2-positive breast cancer. This study will enable further characterization of the safety profile for Tukysa and its long-term safety.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Tukysa Product Monograph meet the necessary regulatory labelling, plain language and design element requirements. A Look-alike Sound-alike brand name assessment was performed and the proposed name Tukysa was accepted.
Overall, Tukysa has been shown to have a favourable benefit-risk profile based on non-clinical and clinical studies and represents a new treatment option for patients with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases. Notably, Tukysa is the first drug to show an improvement in median OS in the post-T-DM1 treatment setting.
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 Tukysa?
The New Drug Submission (NDS) for Tukysa was reviewed under Project Orbis. Project Orbis provides a framework for concurrent submission and review of oncology products as well as information sharing among regulators from multiple jurisdictions. Health Canada, the United States Food and Drug Administration (FDA), Switzerland's Swiss Medic, Singapore's Health Sciences Authority, and Australia's Therapeutic Goods Administration participated in the review of the NDS for Tukysa. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently. The Canadian regulatory decision on the review of Tukysa was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the FDA was used as an added reference.
Due to the collaborative nature of submissions reviewed under Project Orbis and the need to align submission filing dates as closely as possible with international regulatory partners, Health Canada allowed Seattle Genetics Inc. to submit the NDS for Tukysa while the Priority Review request was still under consideration.
The NDS for Tukysa was reviewed under the Priority Review Policy. The NDS for Tukysa met the criteria for Priority Review Status, as substantial evidence of clinical effectiveness was provided for the treatment of a disease that is not adequately managed by drugs marketed in Canada. For HER2-positive metastatic breast cancer patients, there were no approved therapies in Canada that demonstrated clinically meaningful improvement in progression-free survival or overall survival after progression of second-line therapy (T-DM1). Further, patients with brain metastases have traditionally been excluded from participation in clinical trials.
Submission Milestones: Tukysa
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-09-19 |
| Request for priority status | |
| Filed: | 2019-12-12 |
| Approval issued by Director, Bureau of Medical Sciences: | 2020-01-21 |
| Submission filed: | 2020-01-20 |
| Screening | |
| Screening Deficiency Notice issued: | 2020-01-24 |
| Response filed: | 2020-01-31 |
| Screening Acceptance Letter issued: | 2020-02-07 |
| Review | |
| Biostatistics Evaluation complete: | 2020-04-17 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-04-21 |
| Review of Risk Management Plan complete: | 2020-05-01 |
| Quality Evaluation complete: | 2020-05-07 |
| Clinical/Medical Evaluation complete: | 2020-06-02 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2020-06-05 |
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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Tucatinib, the medicinal ingredient in Tukysa, is a reversible and selective tyrosine kinase inhibitor of the human epidermal growth factor receptor (HER) 2. In cellular signaling assays, tucatinib is >1,000-fold more selective for HER2 compared to the closely related kinase epidermal growth factor receptor (EGFR). In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream cell signaling and cell proliferation, and induces death in HER2-driven tumour cells. In vivo, tucatinib inhibits the growth of HER2-driven tumours. The combination of tucatinib and trastuzumab has shown enhanced anti-tumour activity in vitro and in vivo compared to either drug alone. In an intracranial mouse tumour model, tucatinib demonstrated increased distribution to tumour tissue compared to brain parenchyma, and resulted in increased survival.
Tucatinib is metabolized primarily by cytochrome P450 (CYP) 2C8, and to a lesser extent via CYP3A. Concomitant use of tucatinib with moderate or strong CYP2C8 inhibitors or inducers, or strong CYP3A inducers can alter tucatinib exposure. Based on drug-drug interaction studies, tucatinib is a strong inhibitor of CYP3A, and a weak inhibitor of P-glycoprotein and CYP2C8. Tucatinib inhibits multidrug and toxin extrusion protein (MATE) 1- and MATE2-K-mediated transport of metformin and organic cation transporter (OCT) 2- and MATE1-mediated transport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1.
Single and multiple dose pharmacokinetics of tucatinib at 300 mg twice daily has been characterized as monotherapy or in combination with trastuzumab and capecitabine in healthy volunteers and patients with metastatic breast cancer.
Following a single oral dose of 300 mg tucatinib, the median time to peak plasma concentration was approximately 2.0 hours (range: 1.0 to 4.0 hours). Concomitant food intake had no clinically meaningful effect on tucatinib exposure. Tucatinib was cleared from plasma with a mean half-life of approximately 8.7 hours and apparent clearance of 148 L/h in healthy volunteers.
In patients with metastatic breast cancer, following the administration of 300 mg tucatinib twice daily, the estimated half-life and estimated apparent clearance of tucatinib was approximately 9.6 hours and 57.3 L/h, respectively. Steady state was achieved after 4 days of dosing in patients, with less than a 2-fold accumulation. Plasma tucatinib exposure, measured as area under the curve to infinite time (AUC0-inf) and maximum serum concentration (Cmax), demonstrated approximately dose proportional increases at oral doses from 50 to 300 mg twice daily (0.17 to 1 times the recommended dose) administered alone in healthy volunteers. Tucatinib exhibited 1.7-fold accumulation for AUC and a 1.5-fold accumulation for Cmax following administration of Tukysa 300 mg twice daily for 14 days in patients with metastatic breast cancer. Time to steady state was approximately 4 days.
The apparent volume of distribution of tucatinib was approximately 1,670 L in healthy volunteers. The plasma protein binding was 97.1% at clinically relevant concentrations. In plasma, approximately 75.6% of the plasma radioactivity was unchanged tucatinib, 19.3% was attributed to identified metabolites including 9.2% as an active metabolite ONT-993, and 5.1% was unassigned.
Tucatinib is predominantly eliminated by the hepatobiliary route (85.8%), with renal excretion as a minor route (4.1%). No starting dose adjustment is required in patients with mild to moderate renal impairment. Tukysa in combination with capecitabine and trastuzumab cannot be used in patients with severe renal impairment as capecitabine is contraindicated in patients with severe renal impairment. Based on population pharmacokinetic analyses, age, albumin, body weight, and race did not have a clinically meaningful effect on tucatinib exposure. In addition, the effect of gender on tucatinib pharmacokinetics is unknown.
Based on a hepatic impairment study, mild or moderate hepatic impairment has no significant impact on tucatinib exposure, while the AUC0-inf increased 1.6-fold in individuals with severe hepatic impairment compared to those with normal hepatic function. A reduction in starting dose is recommended for patients with severe hepatic impairment.
In a randomised, partially double-blind, placebo- and positive-controlled three-way crossover electrocardiograph (ECG) assessment study in 50 healthy volunteers, tucatinib, administered as 300 mg twice daily for 4 days and then as a single 300 mg dose on the morning of the fifth day, did not have any clinically relevant effect on the QTcF interval (corrected QT interval by Fridericia), the QRS duration, the PR interval, or ventricular heart rate. In this study, the geometric mean (CV%) Cmax value of tucatinib was 519 ng/mL (26.7%).
Overall, the clinical pharmacological data support the intended use of tucatinib in combination with trastuzumab and capecitabine in the target population. Key clinical pharmacology findings, relevant risks, and uncertainties are adequately addressed in the Tukysa Product Monograph.
For further details, please refer to the Tukysa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Tukysa (tucatinib) for the proposed indication was supported primarily by the pivotal randomized, double-blinded, placebo-controlled, active comparator, global Phase II HER2CLIMB study, also known as Study ONT-380-206. The patients enrolled in the HER2CLIMB study were required to have HER2-positive unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and to have had prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. All patients had received at least one prior HER2-directed agent in the metastatic setting, with 94% of patients having had prior trastuzumab treatment, 91% of patients with prior pertuzumab treatment, and 99% of patients with prior T-DM1 treatment in the metastatic setting. HER2 overexpression or amplification was confirmed by central laboratory analysis prior to patient enrollment. Based on data from a supportive Phase I study (ARRAY-380-101), the dose-limiting toxicity of tucatinib as monotherapy was found to be a reversible Grade 3 elevation of transaminases. As a result, the HER2CLIMB protocol excluded patients with chronic liver disease or abnormal liver function tests.
In the HER2CLIMB study, a total of 612 patients were randomized in a 2:1 ratio to receive either Tukysa in combination with trastuzumab and capecitabine (number of patients [n] = 410) or placebo in combination with trastuzumab and capecitabine (n = 202). Eligible patients received treatment administered in cycles of 21 days each. Tukysa (300 mg) or placebo (300 mg) was given orally twice daily for a total of 600 mg/day. Capecitabine was administered at 1,000 mg/m2 orally twice per day on Days 1 through 14 of each 21-day cycle. Trastuzumab was administered intravenously as a loading dose of 8 mg/kg on Day 1 of the first 21-day cycle, and then maintained at a dose of 6 mg/kg on Day 1 of each subsequent 21-day cycle. An alternate dosing option for trastuzumab was a fixed dose of 600 mg administered subcutaneously on Day 1 of each 21-day cycle, except in specific circumstances where it was given weekly to compensate for modifications in treatment schedule. Randomization was stratified by the presence or history of brain metastases (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), and region (Canada, the United States, or the rest of the world).
The primary efficacy endpoint was progression-free survival (PFS) in the first 480 randomized patients, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. Secondary efficacy endpoints were evaluated in all randomized patients (n = 612) and included overall survival (OS), PFS among patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).
The median duration of exposure was 7.3 months (range: <0.1, 35.1) for the tucatinib treatment arm, and 4.4 months (range: <0.1, 24.0) for the placebo treatment arm. After a median duration of follow-up of 10.4 months, there was a statistically and clinically significant reduction of 46% in the risk of a PFS event in patients treated with tucatinib compared to the placebo treatment arm, as assessed by the BICR with a hazard ratio (HR) of 0.54 (95% confidence interval [CI]: 0.42, 0.71); p <0.00001. This corresponded to an increase in the median PFS from 5.6 months in the placebo treatment arm to 7.8 months in the Tukysa treatment arm. The key alpha-controlled secondary efficacy endpoints also statistically and significantly favoured the Tukysa treatment arm, with OS HR of 0.66 (95% CI: 0.50, 0.87; p = 0.0048), representing an increase in the median OS from 17.4 months for the placebo treatment arm to 21.9 months for the Tukysa treatment arm. Progression-free survival in patients with brain metastases at baseline had a HR of 0.48 (95% CI : 0.34, 0.69), with a corresponding median PFS of 7.6 months in the Tukysa treatment arm compared to 5.4 months in the placebo treatment arm.
Additionally, the confirmed ORR by BICR in patients with measurable disease was 40.6% (95% CI: 35.3, 46.0) for the Tukysa treatment arm and 22.8% (95% CI: 16.7, 29.8) for the placebo treatment arm. Efficacy results were consistent across all patient subgroups including hormone receptor status, presence or history of brain metastases, ECOG status, and region.
Post-hoc exploratory analyses performed specifically in patients with brain metastases were supportive of the primary efficacy analyses, and suggest that tucatinib has activity directly on brain metastases. As a result of these exploratory analyses, there was a reported 68% reduction in the risk of disease progression or death (HR = 0.32 [95% CI: 0.216, 0.479]) when PFS for brain metastases only was assessed, with a corresponding increase in the median PFS from 4.2 months in the placebo treatment arm to 9.9 months in the Tukysa treatment arm in this subgroup of patients. Additionally, there was a clinically meaningful improvement in ORR, from 20.0% to 47.3% in the placebo and tucatinib treatment arms, respectively, when considering only brain lesions.
Indication
The New Drug Submission for Tukysa was filed by the sponsor with the following indication:
- Tukysa (tucatinib) is indicated in combination with trastuzumab and capecitabine, for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least 3 prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting.
To more accurately reflect the patient population in the pivotal study, Health Canada approved the following indication:
- Tukysa (tucatinib) is indicated in combination with trastuzumab and capecitabine for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine, separately or in combination.
- Clinical trial data supporting the effectiveness of Tukysa in combination with trastuzumab and capecitabine are limited to patients who had received at least one prior HER2-directed therapy in the metastatic setting.
For more information, refer to the Tukysa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Tukysa (tucatinib) was based primarily on data from the pivotal randomized, double-blinded, placebo-controlled, active comparator, global Phase II HER2CLIMB study described in the Clinical Efficacy section.
Treatment-emergent adverse events (TEAEs) were observed in nearly all patients enrolled in the study, and the overall incidence of TEAEs was similar between Tukysa and placebo treatment arms. The most common TEAEs in the Tukysa treatment arm (≥20%) were diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, increased blood bilirubin, increased alanine aminotransaminase (ALT), increased aspartate aminotransferase (AST), headache, abdominal pain, anemia, and rash.
Adverse events (AEs) were graded from least severe (Grade 1) to most severe (Grade 5). Adverse events ≥Grade 3 occurred in approximately half of the patients enrolled in the HER2CLIMB study, and were slightly higher in the Tukysa treatment arm, compared to the placebo treatment arm. The most common Grade 3 and 4 AEs in the Tukysa treatment arm (≥5%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, hepatotoxicity, increased ALT, and fatigue.
Serious adverse events (SAEs) were balanced between the two treatment arms. The most commonly reported SAEs (≥2%) in patients in the Tukysa treatment arm were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). The TEAEs leading to dose interruption, reduction, and discontinuation were all more commonly reported in the Tukysa treatment arm compared to the placebo treatment arm. However, dose discontinuation was relatively infrequent, occurring in 6% of patients in the Tukysa treatment arm.
Severe diarrhea and severe hepatotoxicity are identified as important safety signals for tucatinib. Diarrhea led to Tukysa dose reductions in 6% of patients and discontinuation in 1% of patients. Two patients in the Tukysa treatment arm experienced a TEAE of Grade 4 diarrhea. Both of these patients died, with diarrhea as a contributor to death. Hepatotoxicity led to Tukysa dose reductions in 8% of patients and discontinuation in 1.5% of patients. Severe hepatotoxicity occurred in 2% of patients in the Tukysa arm, where AST and ALT were ≥10 times the upper limit of normal. There were no cases of hepatotoxicity leading to liver failure or death.
Appropriate warnings and precautions are in place in the Tukysa 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:
- Tukysa in combination with trastuzumab and capecitabine can cause severe diarrhea, leading to dehydration, acute kidney injury, and death. Antidiarrheal treatment may be indicated.
- Tukysa can cause severe hepatotoxicity; monitor transaminase, and bilirubin.
- Tukysa may cause fetal harm and developmental malformation when administered to a pregnant woman.
Overall, the safety profile of Tukysa is considered acceptable for its intended indication. Adverse events are typically manageable through dose reduction, temporary treatment discontinuation, and/or standard medical care. Instructions and recommendations have been included in the Tukysa Product Monograph to promote its safe and effective use.
For more information, refer to the Tukysa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical data support the use of tucatinib (the medicinal ingredient in Tukysa) for the specified indication.
In accordance with the International Council for Harmonisation (ICH) guidance Non-clinical Evaluation for Anticancer Pharmaceuticals, the toxicity of tucatinib has been assessed in non-clinical studies to support its use in the treatment of patients with locally advanced or metastatic HER2-positive breast cancer.
The primary targets of tucatinib in toxicity studies were the gastrointestinal tract, liver, and female and male reproductive organs. In rats and cynomolgus monkeys, gastrointestinal toxicity was dose-limiting, generally associated with lower body weights at higher doses, and was more prominent in cynomolgus monkeys compared to rats. Diarrhea has also been observed with other agents targeting members of the HER family, with agents targeting EGFR having a greater risk of diarrhea than agents targeting HER2.
Tukysa administered orally to rats at doses ≥6 mg/kg/day resulted in higher ALT and alkaline phosphatase, centrilobular hepatocyte hypertrophy, increased interstitial cells in the ovary, atrophy of the uterus, mucification of the vagina, and lobular atrophy of the mammary gland in males. Additional changes included minimally higher liver weights at doses ≥20 mg/kg/day and lower uterus/cervix and prostate gland weights in females and males, respectively. There were no test article-related findings at the end of recovery with the exception of the change in weight to the ovaries of females at doses ≥20 mg/kg/day. The exposure achieved at a dose of 6 mg/kg/day is approximately 2% of the exposure achieved at the maximum recommended human dose of 300 mg twice daily, based on AUC comparison.
Tucatinib administered orally to cynomolgus monkeys at doses ≥5 mg/kg/day resulted in fecal abnormalities and increased heart rates (at vital signs measurement only). Additional findings at a dose of 40 mg/kg/day included transient body weight loss, lean body condition, increased liver weights, and apparent blood in the stool, which was successfully treated with antibiotic therapy. All changes were reversible. In this study, the dose of 20 mg/kg/day is approximately 24% of the maximum recommended human dose of 300 mg twice daily, based on AUC comparison.
In repeat-dose toxicity studies in rats, decreased corpora lutea/corpus luteum cyst, increased interstitial cells of the ovary, atrophy of the uterus, and mucification of the vagina were observed at doses ≥6 mg/kg/day administered twice daily, which resulted in exposures based on AUC0-12 of approximately 4% of the human exposure at the recommended dose. Changes in male rats included lobular atrophy of the male mammary gland and decreased prostate gland weights. No histological effects were observed on male or female reproductive tracts in cynomolgus monkeys or on male reproductive tracts in rats at doses resulting in exposures up to 8 times (in monkeys) or 18 times (in rats) the human exposure at the recommended dose, based on AUC0-12.
Embryo-fetal development studies were conducted in rabbits and rats. Tucatinib administered to pregnant dams caused teratogenicity in rabbits and embryo-fetal toxicity in rats. In pregnant rabbits, increased resorptions, decreased percentages of live fetuses, and skeletal, visceral, and external malformations were observed in fetuses at doses ≥90 mg/kg/day. At this dose, maternal exposure is approximately equivalent to the human exposure at the recommended dose, based on AUC. In pregnant rats, decreased maternal body weight and body weight gain were observed at doses ≥90 mg/kg/day. Fetal effects of decreased weights and delayed ossification were observed at doses ≥120 mg/kg/day.
Carcinogenicity studies have not been conducted with tucatinib. Tucatinib was not mutagenic in an in vitro bacterial reverse-mutation study (Ames test) or clastogenic in either an in vitro mouse bone marrow chromosomal aberration assay or an in vivo mouse bone marrow erythrocyte micronucleus assay.
Appropriate warnings and precautionary measures are in place in the Tukysa Product Monograph to address the identified safety concerns. For more information, refer to the Tukysa 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 Tukysa has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored between 20ºC to 25ºC.
Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation limits and/or qualified from toxicological studies). All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
None of the excipients used in the formulation of Tukysa is of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TUKYSA | 02499827 | SEAGEN INC. | TUCATINIB 50 MG |
| TUKYSA | 02499835 | SEAGEN INC. | TUCATINIB 150 MG |