Summary Basis of Decision for Mektovi
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 Mektovi is located below.
Recent Activity for Mektovi
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.
The following table describes post-authorization activity for Mektovi, a product which contains the medicinal ingredient binimetinib. 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.
Updated: 2023-07-12
Drug Identification Number (DIN):
DIN 02513080 - 15 mg binimetinib, tablet, oral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02513080) market notification | Not applicable | Date of first sale: 2021-07-05 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 237410 | 2020-03-20 | Issued NOC 2021-03-02 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Mektovi
Date SBD issued: 2021-06-08
The following information relates to the New Drug Submission for Mektovi.
Binimetinib
Drug Identification Number (DIN):
- DIN 02513080 - 15 mg binimetinib, tablet, oral administration
Pfizer Canada ULC
New Drug Submission Control Number: 237410
On March 2, 2021, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Mektovi.
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 Mektovi, in combination with encorafenib, is favourable for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
1 What was approved?
Mektovi (binimetinib) is a protein kinase inhibitor. It was authorized for use in combination with another protein kinase inhibitor, encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
Clinical data supporting the use of Mektovi in the treatment of patients with BRAF V600 mutations are limited to patients with V600E or V600K mutations.
The safety and effectiveness of Mektovi have not been established in pediatric (younger than 18 years of age) patients. Therefore, Health Canada has not authorized an indication for pediatric use.
No overall differences in the safety or effectiveness of Mektovi used in combination with encorafenib were observed in patients over 65 years of age compared to younger patients.
Mektovi 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.
Mektovi 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.
Mektovi (15 mg binimetinib) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate of vegetable origin, and microcrystalline cellulose. The tablet coating contains ferric oxide yellow, ferrosoferric oxide, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
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 Mektovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Mektovi approved?
Health Canada considers that the benefit-harm-uncertainty profile of Mektovi, in combination with encorafenib, is favourable for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
Clinical data supporting the use of Mektovi in the treatment of patients with BRAF V600 mutations are limited to patients with V600E or V600K mutations.
Melanoma is the most lethal form of skin cancer due to its propensity to metastasize to vital organs, including the brain, lungs, liver, and other visceral organs. Exposure to ultraviolet light, including history of severe sunburns and exposure to indoor tanning are among risk factors for melanoma. Caucasians are at a higher risk of developing melanoma than other populations. According to the Canadian Cancer Society, approximately 8,200 Canadians will be diagnosed with melanoma in 2021. It is estimated that more than 1,000 Canadians die from melanoma each year.
Approximately 50% of patients with metastatic melanoma have mutations in the BRAF gene (B-Raf proto-oncogene, serine/threonine kinase). Over 95% of these mutations are in BRAF exon 15 at V600 (the amino acid valine at position 600). The most common V600 mutations are V600E and V600K accounting for 66-91% and 7-30% of all BRAF V600 mutations, respectively. These mutations lead to constitutive activation of the BRAF protein and downstream signal transduction in the mitogen-activated protein kinase (MAPK) intracellular signalling pathway (also referred to as RAS/RAF/MEK/ERK signalling pathway), promoting the proliferation and survival of cancer cells. In a prospective study of 197 patients with metastatic melanoma, BRAF mutations were associated with features of high-risk melanoma including truncal location of the primary tumour, earlier age of onset, lack of chronic skin damage, and shortened survival. Current treatment options for patients with BRAF V600-mutant advanced melanoma include immune checkpoint inhibitors and combinations of BRAF and MEK inhibitors.
Binimetinib, the medicinal ingredient in Mektovi, is an adenosine triphosphate (ATP)-uncompetitive, reversible inhibitor of the mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK2 activity. The MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway.
The clinical efficacy and safety of Mektovi in combination with encorafenib (a BRAF inhibitor) were supported by data derived from a pivotal Phase III, randomized, active-controlled, open-label study (COLUMBUS), conducted in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Patients were randomized in a ratio of 1:1:1 to receive Mektovi 45 mg twice daily in combination with encorafenib 450 mg once daily (Combo 450 treatment arm), encorafenib 300 mg once daily (encorafenib treatment arm), or vemurafenib 960 mg twice daily (vemurafenib treatment arm). Treatment continued until disease progression or unacceptable toxicity occurred.
The primary efficacy endpoint was progression-free survival, as assessed by a blinded independent central review, for patients treated with Mektovi in combination with encorafenib compared to patients treated with vemurafenib. A statistically and clinically significant improvement in progression-free survival was observed in patients treated with Combo 450 as compared to patients treated with vemurafenib. The median progression-free survival times were 14.9 months (95% confidence interval [CI]: 11.0, 18.5) in patients treated with Combo 450 and 7.3 months (95% CI: 5.6, 8.2) in patients treated with vemurafenib, which corresponded to a hazard ratio of 0.54 (95% CI: 0.41, 0.71; one-sided stratified log-rank p<0.001).
Secondary efficacy endpoints, including objective response rate, duration of response, and overall survival, while not tested in the protocol-specified hierarchical testing strategy, were supportive of a clinical benefit of the Combo 450 treatment compared to the vemurafenib treatment.
The reported safety data from the Columbus study, based on a median duration of treatment of 51.2 weeks in the Combo 450 arm and 27.1 weeks in the vemurafenib arm, were consistent with data previously reported for patients treated with other combinations of MEK and BRAF inhibitors.
In patients who received Mektovi in combination with encorafenib, the most common adverse reactions (observed in at least 20% of patients) were fatigue, nausea, diarrhea, vomiting, constipation, abdominal pain, headache, rash, hyperkeratosis, increased blood creatinine kinase, arthralgia, myopathy, and visual impairment.
A Serious Warnings and Precautions box has been included in the Mektovi Product Monograph to highlight the following significant adverse reactions identified as driven by Mektovi: left ventricular dysfunction, venous thromboembolism, major hemorrhagic events, retinal pigment epithelial detachment and retinal vein occlusion, interstitial lung disease, and rhabdomyolysis.
A Risk Management Plan (RMP) for Mektovi was submitted by Pfizer Canada ULC 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Mektovi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Mektovi was accepted.
Overall, the safety profile of Mektovi in combination with encorafenib is considered acceptable for the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions including recommendations for dose modifications, are in place in the Mektovi Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Mektovi?
Submission Milestones: Mektovi
| Submission Milestone | Date |
|---|---|
| Submission filed | 2020-03-20 |
| Screening | |
| Screening Acceptance Letter issued | 2020-05-07 |
| Review | |
| Review of Risk Management Plan complete | 2020-11-28 |
| Biopharmaceutics Evaluation complete | 2020-12-10 |
| Non-Clinical Evaluation complete | 2021-02-12 |
| Labelling Review complete | 2021-02-25 |
| Quality Evaluation complete | 2021-02-26 |
| Clinical/Medical Evaluation complete | 2021-03-01 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-03-02 |
The Canadian regulatory decision on the review of Mektovi was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications 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
The pharmacokinetics of binimetinib, the medicinal ingredient in Mektovi, was studied in healthy subjects and patients with solid tumours.
After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to the maximum observed plasma concentration (Tmax) of 1.6 hours. The mean (percent coefficient of variation [CV%]) terminal half-life of binimetinib was 3.5 hours (28.5%) and the mean (CV%) apparent clearance was 20.2 L/h (24%). After twice-daily dosing, binimetinib exhibited 1.5-fold accumulation. The systemic exposure of binimetinib is approximately dose proportional. Concomitant food intake has no significant effect on the pharmacokinetic properties of binimetinib.
Binimetinib is eliminated primarily by metabolism in the liver. In a dedicated clinical study, mild hepatic impairment had no clinically meaningful effect on the exposure of binimetinib. However, compared to subjects with normal liver function, subjects with moderate or severe hepatic impairment had a twofold higher total binimetinib exposure (as measured by the area under the concentration-time curve [AUC]) and a threefold higher exposure of unbound binimetinib. Mektovi in combination with encorafenib is not recommended in patients with moderate or severe hepatic impairment.
Binimetinib is metabolized mainly through glucuronidation, mediated by the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Different UGT1A1 genotypes and smoking (an established UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. No differences in binimetinib exposure have been observed when binimetinib is coadministered with encorafenib (a UGT1A1 inhibitor). Physiologically based pharmacokinetic simulations predict a low potential for clinically significant drug interactions between binimetinib and atazanavir (a UGT1A1 inhibitor). As this has not been evaluated in a formal clinical study, UGT1A1 inducers or inhibitors should be administered with caution.
Binimetinib undergoes limited renal elimination (6.5% of binimetinib is excreted unchanged in the urine). In a dedicated clinical study, no clinically important changes in the exposure of binimetinib were observed in subjects with severe renal impairment (estimated glomerular filtration rate ≤29 mL/min/1.73 m2) compared to subjects with normal renal function. No dose adjustment is recommended for patients with baseline renal impairment.
In population pharmacokinetic analyses, age (range 20 to 94 years), sex, or body weight (range 42 to 168 kg) did not have a clinically important effect on the systemic exposure of binimetinib.
Binimetinib administered alone is not associated with QT prolongation at the recommended therapeutic dose. The addition of binimetinib mitigated some toxicities of encorafenib, likely by blocking the paradoxical activation of the mitogen-activated protein kinase (MAPK) signalling pathway induced by encorafenib.
Overall, the clinical pharmacology data support the intended use of Mektovi in combination with encorafenib for the specified indication.
For further details, please refer to the Mektovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Mektovi in combination with encorafenib was evaluated in a pivotal Phase III, randomized, active-controlled, open-label study (COLUMBUS), conducted in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Patients enrolled were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was not allowed. Patients were randomized (1:1:1) to receive Mektovi 45 mg twice daily in combination with encorafenib 450 mg once daily (Combo 450 treatment arm), encorafenib 300 mg once daily (encorafenib treatment arm), or vemurafenib 960 mg twice daily (vemurafenib treatment arm). Treatment continued until disease progression or unacceptable toxicity occurred.
The primary efficacy endpoint was progression-free survival, as assessed by a blinded independent central review, for patients treated with Mektovi in combination with encorafenib compared to patients treated with vemurafenib. Additional efficacy measures included overall survival, objective response rate, and duration of response, which were also assessed by a blinded independent central review.
The study demonstrated a statistically and clinically significant improvement in progression-free survival in patients treated with Combo 450 as compared to patients treated with vemurafenib. The median progression-free survival times were 14.9 months (95% confidence interval [CI]: 11.0, 18.5) in patients treated with Combo 450 and 7.3 months (95% CI: 5.6, 8.2) in patients treated with vemurafenib, which corresponded to a hazard ratio (HR) of 0.54 (95% CI: 0.41, 0.71; one-sided stratified log-rank p<0.001).
The confirmed objective response rate per central review was 63.0% (95% CI: 55.8%, 69.9%) in the Combo 450 treatment arm compared to 40.3% (95% CI: 33.3%, 47.6%) in the vemurafenib treatment arm.
Responses were durable, with a median duration of response for confirmed responses per central review of 16.6 months (95% CI: 12.2, 20.4) in patients treated with Combo 450 and 12.3 months (95% CI: 6.9, 16.9) in patients treated with vemurafenib.
In an interim analysis of the endpoint of overall survival, performed as per study protocol when 232 events had been observed in the Combo 450 and vemurafenib arms combined, the overall survival data were analyzed descriptively without formal statistical significance testing, due to the protocol-specified hierarchical testing rules. An estimated 39% reduction in the risk of death was observed for patients randomized to the Combo 450 arm compared to those randomized to the vemurafenib arm (HR = 0.61; 95% CI: 0.47, 0.79), with median (95% CI) overall survival of 33.6 months (24.4, 39.2) and 16.9 months (14.0, 24.5), respectively.
Indication
The New Drug Submission for Mektovi was filed by the sponsor with the following indication:
- Mektovi (binimetinib) is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Upon review of the submitted data, Health Canada revised the proposed indication to: i) refer to a validated test for detection of the BRAF V600 mutations and ii) include a caveat statement reflecting the patient population studied. Accordingly, Health Canada approved the following indication:
- Mektovi is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
-
Clinical data supporting the use of Mektovi in the treatment of patients with BRAF V600 mutations are limited to patients with V600E or V600K mutations.
For more information, refer to the Mektovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety evaluation of Mektovi in combination with encorafenib is based primarily on data from 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who were treated with Mektovi (45 mg twice daily) in combination with encorafenib (450 mg once daily) in the randomized, open-label, active-controlled COLUMBUS study (described in the Clinical Efficacy section). Based on a median duration of treatment of 51.2 weeks, the safety data were consistent with data previously reported for patients treated with other combinations of MEK and BRAF inhibitors.
In patients who received Mektovi in combination with encorafenib, the most common adverse reactions (observed in at least 20% of patients) were fatigue, nausea, diarrhea, vomiting, constipation, abdominal pain, headache, rash, hyperkeratosis, increased blood creatinine kinase, arthralgia, myopathy, and visual impairment.
Important identified toxicities associated with Mektovi include left ventricular dysfunction, venous thromboembolism, major hemorrhagic events, retinal pigment epithelial detachment and retinal vein occlusion, interstitial lung disease, and rhabdomyolysis.
Fewer patients receiving Mektovi in combination with encorafenib (57.8%) experienced grade 3/4 adverse events compared to patients receiving vemurafenib (63.4%).
A slightly higher proportion of patients in the vemurafenib arm (37.1%) experienced at least one serious adverse event compared to the Mektovi in combination with encorafenib arm (34.4%). The most commonly reported serious adverse events in the Mektovi in combination with encorafenib arm were pyrexia, abdominal pain, anemia, acute kidney injury, cerebral hemorrhage, general physical health deterioration, pneumonia, pulmonary embolism, and vomiting.
Adverse reactions requiring dose interruptions of Mektovi occurred in 33% of patients receiving Mektovi in combination with encorafenib. The dose interruptions were most commonly due to left ventricular dysfunction (6%) and serous retinopathy (5%).
Adverse reactions leading to dose reductions of Mektovi occurred in 19% of patients receiving Mektovi in combination with encorafenib. The most common adverse reactions that resulted in dose reductions were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%).
Adverse reactions led to permanent discontinuation of Mektovi in 5% of patients receiving Mektovi in combination with encorafenib. Hemorrhage (2%) and headache (1%) were the most common adverse reactions requiring permanent discontinuation of Mektovi.
Appropriate warnings and precautionary measures, including recommendations for dose modifications, are in place in the Mektovi Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box highlights the following significant adverse reactions identified as driven by Mektovi: left ventricular dysfunction, venous thromboembolism, major hemorrhagic events, retinal pigment epithelial detachment and retinal vein occlusion, interstitial lung disease, and rhabdomyolysis.
For more information, refer to the Mektovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Binimetinib, the medicinal ingredient in Mektovi, is an adenosine triphosphate (ATP)-uncompetitive, reversible inhibitor of the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2 activity. The MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway.
In vitro, in cell-free assays, binimetinib inhibited ERK phosphorylation. In cultured cells, binimetinib inhibited MEK-dependent phosphorylation and viability of BRAF-mutant human melanoma cell lines.
In vivo, binimetinib inhibited ERK phosphorylation and tumour growth in BRAF-mutant human melanoma xenograft models.
Binimetinib (a MEK inhibitor) and encorafenib (a BRAF inhibitor) target two different kinases in the RAS/RAF/MEK/ERK signalling pathway. In comparison to either drug when administered alone, the combination of binimetinib and encorafenib resulted in greater antiproliferative activity in vitro in BRAF mutation-positive cell lines and greater antitumour activity in vivo in BRAF V600E-mutant human melanoma xenograft models. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E-mutant human melanoma xenografts in nude mice.
The toxicological evaluations of binimetinib were conducted in rats and monkeys. In rats, the major target organ of toxicity was the skin, consistent with the severe dermatologic reactions reported clinically. The major target organ of toxicity in monkeys was the gastrointestinal tract.
Carcinogenicity studies with binimetinib have not been conducted. In standard genotoxicity studies, binimetinib did not exhibit genotoxicity.
In reproductive toxicity studies, administration of binimetinib to pregnant rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses ≥30 mg/kg/day (approximately 37 times the human exposure achieved at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses ≥10 mg/kg/day (approximately 5 times the human exposure achieved at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily).
The results of the non-clinical studies as well as the potential risks to humans have been included in the Mektovi Product Monograph. In view of the intended use of Mektovi, in combination with encorafenib, there are no pharmacological and toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Mektovi 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 Mektovi 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 60 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits).
The sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (i.e., excipients, described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| MEKTOVI | 02513080 | PFIZER CANADA ULC | BINIMETINIB 15 MG |