Summary Basis of Decision for Mekinist

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Mekinist is located below.

Recent Activity for Mekinist

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 Mekinist

Updated:  2023-04-05

The following table describes post-authorization activity for Mekinist, a product which contains the medicinal ingredient trametinib. 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 Numbers (DINs):

  • DIN 02409623 - 0.5 mg trametinib, tablet, oral administration
  • DIN 02409631 - 1.0 mg trametinib, tablet, oral administration
  • DIN 02409658 - 2.0 mg trametinib, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 256554 2021-09-10 Issued NOC 2022-07-26 Submission filed as a Level I – Supplement to update the PM with data from study COMBI-APlus. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.
SNDS # 255274 2021-07-30 Issued NOC 2021-12-03 Submission filed as a Level II – Supplement (Safety) to update the PM to reflect revised pyrexia management guidance. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 245843 2020-10-29 Issued NOC 2021-03-19 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 232720 2019-10-18 Issued NOC 2020-09-10 Submission filed as a Level I – Supplement to update the PM with follow-up data from study MEK115306. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.
NC # 231497 2019-09-10 Issued NOL 2019-12-06 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, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 223527 2019-01-09 Issued NOL 2019-04-05 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 and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 213580 2018-02-09 Issued NOC
2018-09-21
Submission filed as a Level I - Supplement to extend the indications to include combination therapy for the adjuvant treatment of patients with Stage III melanoma with a BRAF V600 mutation, following resection. Regulatory Decision Summary published.
NC # 213866 2018-02-21 Issued NOL;
2018-06-19
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 section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 210760 2017-10-30 Issued NOC
2018-05-18
Submission filed as a Level I - Supplement for an expanded indication in combination dabrafenib for the treatment of previously untreated (treatment naïve) patients with metastic non-small cell lung cancer (NSCLC) with a BRAF V600 mutation. Regulatory Decision Summary published.
SNDS # 199382 2016-10-18 Issued NOC
2017-05-16
Submission filed as a Level I - Supplement for a new indication in combination with dabrafenib for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600 mutation whose disease has progressed following systemic therapy, and the removal of the 1 mg dosage strength. Regulatory Decision Summary published.
DIN 02409631 cancelled pre-market Not applicable Discontinuation date:
2017-05-15
The manufacturer notified Health Canada that sale of the drug has been discontinued pre-market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
NC # 197849 2016-08-23 Issued NOL
2016-12-06
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Warnings and Precautions section of the PM to include new safety information. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02409623) market notification Not applicable Date of first sale:
2016-07-04
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS-C # 185328 2015-06-11 Issued NOC
2016-05-13
Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. The submission provided final study reports for three clinical trials (studies MEK115306, MEK116513, and BRF113220) to fulfil the post-authorization commitments agreed upon in SNDS # 183167. The benefit-risk profile of Mekinist in combination with dabrafenib is considered positive for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. As a result of the submission, revisions were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, and Clinical Trials sections of the Product Monograph, and corresponding changes were made to Part III: Consumer Information. An NOC was issued.
NC # 189780 2015-11-19 Issued No Objection Letter
2016-03-23
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM). As a result of the Notifiable Change, additions were made to the Warnings and Precautions, Adverse Reactions, and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
SNDS # 183167 2015-03-24 Issued NOC NOC/c
2016-03-11
Regulatory Decision Summary published.
NC # 187865 2015-09-17 Issued No Objection Letter
2016-01-26
Submission filed as a Level II (120 day) Notifiable Change to update the Product Monograph (PM) to reflect revisions in the global data sheet. As a result of the Notifiable Change, revisions were made to the Drug Interactions section of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02409658) market notification Not applicable Date of first sale:
2015-07-31
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS #185240 2015-06-12 Issued NOC
2015-07-31
Submission filed to change the name of the manufacturer from GlaxoSmithKline Inc. to Novaritis Pharmaceuticals Canada Inc.
NC #183880 2015-04-21 Issued No Objection Letter
2015-07-29
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to revise the Product Monograph (PM) by adding the adverse event of venous thromboembolism to the Serious Warnings and Precautions box, Warnings and Precautions, Adverse Reactions and Part III: Consumer Information sections of the PM. Other changes proposed to the PM included updates to the Toxicology section and Reproductive Toxicology section. The submission was reviewed and a No Objection Letter was issued.
NC #178010 2014-10-02 Cancellation Letter Received
2015-01-12
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph in response to an Advisement Letter issued by Health Canada on 2014/09/22. After reviewing additional information, Health Canada did not consider the changes necessary and the sponsor cancelled the submission.
NC # 168514 2013-09-27 Issued No Objection Letter
2013-12-13
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) at the request of the reviewing division, to revise the Product Monograph (PM) with respect to the risk of hypertension. As a result of the NC, revisions were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
Drug product (DINs 02409623, 02409658) market notification Not applicable Date of first sale:
2013-08-28
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 157665 2012-08-03 Issued NOC
2013-07-18
Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Mekinist

Date SBD issued: 2014-02-13

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

Trametinib, 0.5 mg, 1.0 mg and 2.0 mg, tablets, oral

Drug Identification Number (DIN):

  • DIN 02409623 - 0.5 mg tablet
  • DIN 02409631 - 1.0 mg tablet
  • DIN 02409658 - 2.0 mg tablet

GlaxoSmithKline Inc.

New Drug Submission Control Number: 157665

 

On July 18, 2013, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product Mekinist.

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 Mekinist is favourable as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A validated test is required to identify BRAF V600 mutation status.

 

1 What was approved?

 

Mekinist (trametinib), a protein kinase inhibitor of MEK1 and MEK2, was authorized as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A validated test is required to identify BRAF V600 mutation status.

Clinical data supporting the effectiveness of Mekinist in patients with BRAF V600K mutation are limited and fewer responses were reported in BRAF V600K patients compared to BRAF V600E patients. There are no clinical data for other less common BRAF V600 mutations.

Mekinist should not be used in patients who have progressed on a prior BRAF inhibitor therapy.

Mekinist has not been compared with a BRAF inhibitor in a clinical study in patients with unresectable or metastatic melanoma.

No overall differences in effectiveness of Mekinist was observed between elderly patients (≥65 years) and younger patients. However, elderly patients reported higher rates of permanent discontinuation and dose reductions/interruptions than the younger patients.

The safety and efficacy of Mekinist have not been established in children and adolescents less than 18 years of age. Toxicology studies in rats showed dose-related thickening of the growth plate and subepiphyseal infarcts/degeneration in long bones. Mekinist is not recommended for use in in children and adolescents.

Mekinist is contraindicated for patients who are hypersensitive to trametinib or to any ingredient in the formulation or component of the container. Mekinist was approved for use under the conditions stated in the Mekinist Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Mekinist, (0.5, 1.0, 2.0 mg, trametinib) is presented as a tablet. In addition to the medicinal ingredient, trametinib, the tablets contain the following non-medicinal ingredients: croscarmellose sodium, hypromellose; magnesium stearate; mannitol, microcrystalline cellulose; silicon dioxide (colloidal); and sodium lauryl sulphate. The tablet coating contains hypromellose polyethylene glycol, and titanium dioxide, and iron oxide yellow (0.5 mg tablets), iron oxide red (2 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets). The Mekinist 1 mg tablets are not available in Canada.

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

 

2 Why was Mekinist approved?

 

Health Canada considers that the benefit/risk profile of Mekinist is favourable as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A validated test is required to identify BRAF V600 mutation status.

Cutaneous melanoma is the most aggressive form of skin cancer. Systematic treatment options for unresectable or metastatic melanoma include cytotoxic chemotherapy, immunotherapy (including interleukin-2 and ipilimumab), and in the case of melanoma with a BRAF V600 mutation, the BRAF inhibitors vemurafenib and dabrafenib.

The pivotal study supporting market authorization was a Phase III randomized open-label study comparing Mekinist to chemotherapy in 322 patients with unresectable or metastatic BRAF V600E or V600K mutation-positive cutaneous melanoma who had received up to one prior chemotherapy for advanced disease. Supportive safety and efficacy data were provided from a Phase II single arm study in BRAF V600E or V600K mutation positive melanoma in the cohort of patients not previously treated with t a BRAF inhibitor, and from a Phase I study in the subset of 30 patients with metastatic melanoma who had not received prior therapy with a BRAF inhibitor.

In the Phase III study, Mekinist demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) representing a 55% reduction in the risk of tumour progression or death for patients treated with Mekinist compared with those treated with chemotherapy. Although an improvement in overall survival (OS) was reported at the time of primary analysis, these OS data (20% events) were immature. The mature OS data with 63% events showed a 22% reduction in the risk of death in the Mekinist arm that was not statistically significant. The median OS was 15.6 months for patients treated with Mekinist and 11.3 months for those treated with chemotherapy. The confirmed overall response rate assessed by investigators was statistically significantly higher in patients treated with Mekinist compared with those treated with chemotherapy [22% versus (vs.) 8%]. However, based on cross-study comparisons in patients with BRAF V600 mutation positive unresectable or metastatic melanoma, the overall response rates observed with Mekinist were much lower than those observed with BRAF inhibitors (~50%), and the point estimates of the PFS and OS hazard ratios tended to be higher.

The treatment effect of Mekinist was consistently observed across all subgroups based on PFS and OS, although overall response rate in patients with BRAF V600K mutation treated with Mekinist was lower compared to those treated with chemotherapy (10% vs. 18%).

In the Phase II study, which enrolled patients with unresectable of metastatic BRAF V600 mutation-positive melanoma into two cohorts (one cohort had prior treatment with a BRAF inhibitor, the other had no prior treatment with a BRAF-inhibitor) a confirmed response rate of 25% was reported for the 57 patients who had not received prior treatment with a BRAF inhibitor. However, none of the 40 patients who had received prior treatment with BRAF inhibitor achieved a response. Therefore, Mekinist should not be used in patients who have progressed on a prior BRAF therapy.

In the Phase I study, the confirmed ORR in patients with BRAF-mutation unresectable or metastatic melanoma was 33%.

The safety profile of Mekinist monotherapy was characterized in 329 patients with melanoma administered Mekinist 2 mg once daily. The most common adverse events occurring in ≥20% of patients treated with Mekinist included rash, diarrhea, fatigue, peripheral edema, nausea, dermatitis acneiform and vomiting. The most commonly reported Grade 3/4 AEs were hypertension and rash. Serious adverse events were reported in 22% of patients, the most common being: cellulitis; pulmonary embolism; anemia; dyspnoea; pneumonitis; vomiting; dehydration; and erysipelas. Adverse events led to dose interruption, reduction and permanent discontinuation in 36%, 26% and 10% of the patients, respectively.

Significant clinical adverse reactions associated with Mekinist were: left ventricular dysfunction; retinal pigment epithelial detachment; retinal vein occlusion; serious skin toxicity; and interstitial lung disease. These adverse reactions are highlighted in a Serious Warnings and Precautions Box and appropriate monitoring and dose modifications are outlined in the Mekinist Product Monograph.

In the randomized pivotal study, among the commonly reported adverse events, rash, diarrhea, edema peripheral, dermatitis acneiform, dry skin, pruritis, paronychia and hypertension were more frequent in the trametinib arm, while nausea, vomiting and constipation were more frequent in the chemotherapy. The frequencies of adverse events, adverse events leading to permanent discontinuation, serious adverse events and fatal adverse events were comparable between the Mekinist arm and chemotherapy arm, while the frequency of Grade 3/4 adverse events, drug-related adverse events, and adverse events leading to dose interruption or reduction were higher in the Mekinist arm than in the chemotherapy arm.

A Risk Management Plan (RMP) for Mekinist was submitted by GlaxoSmithKline Inc. 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.

Overall, the benefits/risk assessment establishes Mekinist as an effective alternative therapeutic option with an acceptable safety profile for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, with the important caveats that it is not effective in patients who have progressed on prior BRAF inhibitor therapy and that Mekinist may not be as effective as BRAF inhibitors.

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 Mekinist?

 

Submission Milestones: Mekinist

Submission Milestone Date
Pre-submission meeting: 2012-05-17
Submission filed: 2012-08-03
Screening  
Screening Acceptance Letter issued: 2012-09-21
Review  
Biopharmaceutics Evaluation complete: 2013-04-10
Quality Evaluation complete: 2013-06-26
Clinical Evaluation complete: 2013-07-18
Biostatistics Evaluation complete: 2013-04-22
Labelling Review complete: 2013-07-16
Notice of -Compliance (NOC) issued by Director General: 2013-07-18

 

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:

 

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

 

Clinical Pharmacology

Trametinib, the medicinal ingredient of Mekinist, is a reversible and selective allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. The proteins, MEK1 and MEK2, are critical components of the mitogen-activated protein kinase (MAPK) pathway. Mutant BRAF proteins signal through MEK1 and MEK2 leading to constitutive activation of the MAPK pathway and stimulation of cell growth. Trametinib inhibited growth of BRAF V600 mutant melanoma cell lines and demonstrated anti-tumour effects in BRAF V600 mutant melanoma xenograft models. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50% of melanoma.

The clinical pharmacokinetics of trametinib were characterized following single and repeat oral doses in patients. Trametinib is absorbed rapidly following oral administration with 72% absolute bioavailability relative to an intravenous microdose. The increase in exposure was dose-proportional following repeat dosing. Administration of a single dose of Mekinist with a high-fat, high-calorie resulted in lower systemic exposure and therefore, administration under fasting condition is recommended. Trametinib has a long terminal half-life (5.3 days) and accumulates with repeat dosing. It is highly bound to plasma proteins (97.4%). Trametinib is metabolized predominantly via deacetylation with oxidation or in combination with glucuronidation biotransformation pathways. Fecal excretion is the major routes of elimination accounting for >80%, while urinary excretion accounts for <19%.

In a population pharmacokinetic analysis, sex and body weight were found to influence trametinib oral clearance. Smaller female patients are predicted to have higher exposure than heavier male patients. Formal drug-drug interaction studies have not been conducted. The potential for drug-drug interactions with trametinib as a perpetrator or victim is low based on in vitro study results.

Formal pharmacokinetic studies in patients with renal impairment or hepatic impairment have not been conducted. Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics given the low renal excretion of trametinib. Based on a population pharmacokinetic analysis, the oral clearance of trametinib in patients with mild hepatic impairment was not significantly different than patients with normal hepatic function. There are no clinical data in patients with moderate or severe hepatic impairment.

A dedicated electrocardiogram study has not yet been completed. The effect of Mekinist on ECG intervals has been evaluated in a Phase I study. In this study, Mekinist was associated with concentration-dependent prolongation of the PR interval. The predicted magnitude of PR interval prolongation is approximately 8 ms at the mean Cmax and 12 ms at the maximum Cmax for a 2 mg QD dose. While concentration-effect analyses did not demonstrate any statistically significant effects for QTc, QRS, or heart rate, the predictive value of PK/PD modeling of ECG parameter data is not well established. The labeling will be updated when the results are available from the dedicated electrocardiogram study that is ongoing.

Overall, the clinical pharmacological data support the use of Mekinist for the authorized indication. Appropriate warnings and precautions are in place in the approved Mekinist Product Monograph to address the gaps.

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

Clinical Efficacy

The primary evidence to support the clinical efficacy of Mekinist (tramatinib) for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma comes from a randomized, Phase III study (MEK114267). Efficacy in patients who had no prior BRAF inhibitor treatment was supported by a Phase II study (MEK113583) evaluating two cohorts of patients: Cohort A had prior treatment with a BRAF inhibitor; Cohort B had no prior treatment with a BRAF inhibitor. No patient in Cohort A achieved a complete or partial response after treatment with Mekinist. Further support for the clinical activity of Mekinist was provided by the subset of 30 patients from a first-time-in-human (FTIH) study (Study MEK111054).

Study MEK114267 was a randomized, two-arm, open-label, international, multicentre Phase III study to evaluate the efficacy and safety of single agent Mekinist compared with chemotherapy. The population included patients with histologically confirmed cutaneous unresectable or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600E or V600K mutation. Patients who have received up to one prior chemotherapy for advanced or metastatic disease and with a history of prior brain metastases were eligible as long as all brain lesions were treated with surgery or stereotactic radiosurgery and if still present, confirmed stable for at least 90 days prior to randomization. Patients randomized 2:1 to receive Mekinist 2 mg once daily under fasting conditions or chemotherapy (dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Treatment for all patients continued until disease progression, death or withdrawal. Patients in the chemotherapy arm were allowed to cross over to Mekinist therapy after independent confirmation of progression.

The Intent to Treat (ITT) population included all randomized patients with BRAF V600E, or V600K mutation-positive unresectable or metastatic melanoma with or without a prior history of brain metastases. The primary efficacy population included patients with BRAF V600E mutation-positive melanoma without a prior history of brain metastases. The primary efficacy endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall response rate (ORR), and duration of response. The primary analysis was to be conducted in the primary efficacy population. Secondary analyses included PFS in the ITT population as well as OS and ORR in both the primary efficacy and ITT populations.

Of note, while MEK114267 was ongoing, and before final data were available for analysis and reporting, data from the Phase II Study MEK113583 were reviewed and suggested that subjects with BRAF V600E mutation-positive melanoma with no history of prior brain metastases showed the greatest benefit with trametinib relative to subjects with BRAF V600K mutations and/or a prior history of brain metastases. Although the pivotal study was fully enrolled at that time, a decision was undertaken to focus the primary analysis of the pivotal study on the population of melanoma subjects who were likely to demonstrate the most favorable benefit risk profile with trametinib treatment. Therefore, prior to database freeze, the primary efficacy analysis population in MEK114267 was changed to BRAF V600E mutation-positive subjects without brain metastases. This action was taken based solely on the review of Phase II data and was done prior to analysis and reporting of the Phase III study.

A total of 1,059 patients were screened and 322 patients with BRAF V600E or V600K mutation-positive cutaneous melanomas were enrolled (ITT population). In the ITT population, the BRAF mutation status was V600E in 281 (87%) patients, V600K in 40 (12%), and V600E/V600K in 1. The number of patients with a history of brain metastases was 11 (3%). The primary efficacy population (V600E status and no history of brain metastases) included 273 patients.

In the primary efficacy population, Mekinist demonstrated a statistically significant improvement in investigator-assessed PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI): 0.31, 0.64; p<0.0001], which represents a 56% reduction in the risk of tumour progression or death for patients treated with Mekinist (number of patients (n) = 178) compared with those treated with chemotherapy (n = 95). Median PFS was 4.8 months in patients treated with Mekinist and 1.4 months in those treated with chemotherapy. Comparable PFS results were observed in the ITT population (HR = 0.45; 95% CI 0.33, 0.63; n = 322; p<0.0001). At the time of the primary analysis, the median duration of follow-up was 4.9 months for patients treated with Mekinist and 4.8 months for those treated with chemotherapy. The PFS results were consistent across various subgroups of patients, including those with or without prior chemotherapy.

At the time of primary analysis, OS data were not mature (with 20% events reported in the ITT population), and 51 (47%) patients in the chemotherapy arm had crossed over to receive Mekinist after disease progression. In the analysis these data in which cross over was ignored, an improvement in OS was observed (HR = 0.54; 95% CI: 0.32, 0.92, p = 0.014). However, in the analysis in which patients were censored at the time of crossover, while the HR was also in favor of Mekinist treatment, the p-value associated with it was greater than 0.05 [HR = 0.59 (0.30, 1.18), p = 0.073]. Further, an updated more mature OS analysis (with 63% events reported) resulted in a non-significant 22% reduction in risk of death (HR = 0.78; 95% CI: 0.57, 1.06, p = 0.09). In this analysis, the observed median OS was 15.6 months for Mekinist and 11.3 months for chemotherapy. Overall, the results for OS were not considered significant.

The investigator-assessed best confirmed ORR was 22% in the Mekinist arm compared to 8% in the chemotherapy arm. Treatment effect with Mekinist was observed across all subgroups with the exception of the subgroup of patients with tumors with the BRAF V600K mutation. In patients with BRAF V600K mutation-positive melanoma, the investigator-assessed best confirmed ORR was 10% in the Mekinist arm (n = 29) compared to 18% in the chemotherapy arm (n = 11). Further, in the Mekinist treatment arm, the confirmed ORR was lower (10%) in patients with BRAF V600K mutation-positive melanoma than in those with BRAF V600E mutation-positive melanoma (24%).

A higher frequency of de novo brain metastasis was reported in the Mekinist arm compared to the chemotherapy arm (12% vs. 4%, respectively). However, a lack of systemic brain imaging together with the shorter duration on study in the chemotherapy arm may explain the lower frequency of de novo brain lesions observed in the chemotherapy arm.

The single arm Phase II study (MEK113583) enrolled 97 patients with BRAF V600 (V600E, or V600K) mutation-positive unresectable or metastatic cutaneous melanoma into two cohorts; Cohort A (n = 40) had prior treatment with a BRAF inhibitor, Cohort B (n = 57) had no prior treatment with a BRAF-inhibitor. Patients were treated with Mekinist 2 mg orally once daily. In Cohort B, the confirmed ORR was 25% (95% CI: 14.1, 37.8%) and the median duration of response of 5.7 months. However, contrary to expectations, in Cohort A, no patient achieved a confirmed response, either complete or partial.

In the Phase I safety study (MEK111054) an exploratory analysis of tumour response in a subgroup of patients with BRAF V600 mutation-positive cutaneous melanoma without prior BRAF inhibitor treatment (n = 30) was conducted. A confirmed ORR of 33% with a duration of response of 5.6 months was reported.

Overall, the efficacy results of Mekinist in the pivotal Phase III study, along with the results of the supportive studies, provide substantial evidence of clinical benefit of Mekinist treatment in unresectable or metastatic BRAF V600 mutation-positive melanoma, with the important caveats that it is of no demonstrated benefit in patients who have progressed on prior BRAF inhibitor therapy and that it may have less benefit than BRAF inhibitor therapies.

The following efficacy concerns are addressed in the Mekinist Product Monograph.

  • Clinical data in patients with BRAF V600K mutation are limited and the reported response rates were lower in BRAF V600K mutation-positive patients compared to BRAF V600E mutation-positive patients.
  • There are no clinical data available to support the efficacy of Mekinist in the treatment of patients with the other rare BRAF V600 mutations.
  • Efficacy of Mekinist has not been compared with a BRAF inhibitor and Mekinist appeared to be less effective than BRAF inhibitors based on cross-trial comparisons of response rates, and to a lesser extent point estimates of PFS and OS hazard ratios. Mekinist demonstrated no activity in patients who had prior treatment with a BRAF inhibitor.

The above information is considered critical for prescribers to make an informed decision for choosing appropriate treatment in patients with BRAF V600 mutation positive unresectable or metastatic melanoma.

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

Clinical Safety

The clinical safety of Mekinist (trametinib) was evaluated in an integrated population of 329 patients with unresectable or metastatic melanoma treated with Mekinist 2 mg orally once daily in clinical studies. The median duration of treatment exposure in these patients was 3.8 (range: 0.03-24.5) months.

Almost all patients (>99%) treated with Mekinist reported at least one adverse event. The most common adverse events (≥20%) reported included rash, diarrhoea, fatigue, peripheral oedema, nausea, dermatitis acneiform and vomiting. Serious adverse events were reported in 22% of patients and the most common serious adverse events were cellulitis, pulmonary embolism, anaemia, dyspnoea, pneumonitis, vomiting, dehydration, and erysipelas.

Adverse events leading to permanent discontinuation of Mekinist were reported in 10% of patients. Adverse events leading to permanent discontinuation included ejection fraction decreased and/or left ventricular dysfunction, pneumonitis, alanine aminotransferase increased, diarrhea, rash, renal failure, and retinal vein occlusion. Adverse events leading to dose reduction of Mekinist were reported in 26% of patients while adverse events leading to dose interruption of Mekinist were reported in 36% of patients. The most common adverse events leading to dose reductions or interruptions/delays included rash, ejection fraction decreased and/or left ventricular dysfunction, dermatitis acneiform, diarrhea, peripheral oedema, and alanine aminotransferase increased.

In the pivotal study (described in the Clinical Efficacy section), the median duration of study treatment was 4.8 (range: 0.3-16.3) months for the Mekinist arm and 2.1 (range: 0.1-14.0) months for chemotherapy arm. The proportion of patients with adverse events resulting in permanent discontinuation of study drug was 12% in the Mekinist treatment group and 9% in the chemotherapy treatment group. The incidence of adverse events leading to dose reduction was 32% in the Mekininst treatment group and 11% in the chemotherapy group while the incidence of adverse events leading to dose delay/interruption was 41% in the Mekinist treatment group and 27% in the chemotherapy group.

Fatal adverse events were reported in 1.9% of patients in the Mekinist treatment group (myocardial infarction, renal failure, hepatic and renal failure, death of unknown cause) and in 2% of chemotherapy-treated patients (pneumonia, pseudomembranous colitis). Two fatal adverse events (infected skin ulcer, pneumonitis) were reported in patients treated with Mekinist after crossover from the chemotherapy arm.

Grade 3 and serious adverse events were reported more frequently by elderly patients than younger patients. In addition, elderly patients were less tolerant of Mekinist treatment with a higher percentage experiencing adverse events leading to dose interruption, reduction or permanent discontinuation. Common and Grade 3 adverse reactions were reported more frequently in female patients than males, which may be related to higher exposure levels of trametinib in females.

Adverse drug reactions that are considered clinically significant include: left ventricular dysfunction, retinal pigment epithelial detachment, retinal vein occlusion, skin toxicity (including serious cases), and interstitial lung disease. These adverse drug reactions have been amended to a Serious Warnings and Precautions box in the Mekinist Product Monograph. Appropriate warnings and precautions, as well as monitoring and dose modifications are in place in the approved Mekinist Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical pharmacology, safety pharmacology, pharmacokinetic, and toxicology program conducted with trametinib is considered to be sufficient to support the anti-cancer clinical indication proposed in adult patients.

Adverse effects in non-clinical studies were generally considered to be the result of the pharmacologic mechanism of action and occurred at systemic exposures that were usually sub-therapeutic.

Non-clinical pharmacology studies demonstrated that trametinib is a reversible allosteric inhibitor of MEK1 and MEK2 activation and kinase activity. It inhibited growth of BRAF V600 (V600E, V600K and V600D) mutation positive melanoma cell lines and demonstrated anti-tumour effects in BRAF V600E mutant melanoma xenograft models.

Pharmacokinetic studies demonstrated that trametinib is metabolized predominantly via deacetylation by hydrolytic enzymes. In microsomes and hepatocytes, trametinib was metabolically stable with low intrinsic clearance. Based on in vitro results, the risk for drug-drug interactions involving cytochrome P450 enzymes and major transporters with trametinib treatment at therapeutic exposure in humans appears low.

In safety pharmacology studies, in vitro, trametinib inhibited human Ether-à-go-go Related Gene (hERG) channel repolarization in a concentration dependent manner while in vivo; a single intravenous infusion of trametinib in dogs produced no changes in electrocardiogram parameters, blood pressure, or heart rate. The findings in toxicology studies are, for the most part, consistent with effects that would be anticipated consequent to the pharmacologic activity of trametinib on proliferating tissues.

Toxicity results suggest risks for adverse effects on fertility and the developing fetus. Effects on growth plates in long bones of growing animals indicate caution is required for the use in children and adolescents. Increases in serum phosphate were associated with tissue mineralization in rats, but not dogs.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Mekinist Product Monograph. In view of the intended use of Mekinist, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Mekinist 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 Mekinist 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 is considered acceptable.

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. The excipients used in the product formulation are not of animal or human origin.