Summary Basis of Decision for Mekinist

 

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 C_max and 12 ms at the maximum C_max 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.