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Mechanism Of Action
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.
Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.
Administration of 1 mg and 2 mg trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis).
The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.
After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively.
Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with fasted conditions [see DOSAGE AND ADMINISTRATION].
Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.
Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases.
Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥ 75% of drug-related material in plasma is the parent compound.
The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h.
Following oral administration of [14C]-trametinib, > 80% of excreted radioactivity was recovered in the feces while < 20% of excreted radioactivity was recovered in the urine with < 0.1% of the excreted dose as parent.
Based on a population pharmacokinetic analysis, age, gender, and body weight do not have a clinically important effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity.
Hepatic Impairment: Based on a population pharmacokinetic analysis in 64 patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1.0 to 1.5 x ULN and any AST), mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations].
Renal Impairment: As renal excretion of trametinib is low ( < 20%), renal impairment is unlikely to have a clinically important effect on the exposure of trametinib. Based on a population PK analysis in 223 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m²) and 35 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m²), mild and moderate renal impairment have no clinically important effects on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with severe renal impairment [see Use in Specific Populations].
Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients.
Based on in vitro studies, trametinib is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or of transporters including human organic anion transporting polypeptide (OATP1B1, OATP1B3), P-gp, and BCRP at a clinically relevant systemic concentration of 0.04 μM. Trametinib is an inhibitor of CYP2C8 in vitro.
Trametinib is an inducer of CYP3A4 in vitro. Based on cross-study comparisons, oral administration of trametinib 2 mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically important effect on the AUC and Cmax of everolimus.
Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of trametinib or hydroxy-dabrafenib as compared with administration of either drug alone.
BRAF V600E Or V600K Mutation-Positive Unresectable Or Metastatic Melanoma
The safety and efficacy of MEKINIST were evaluated in two clinical trials. Trial 1 was an international, multicenter, randomized (2:1), open-label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Trial 2 was a multicenter, randomized (1:1:1), open-label, dose-ranging trial designed to evaluate the clinical activity and safety of MEKINIST (at two different doses) in combination with dabrafenib and to compare the safety with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma.
In Trial 1, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m² intravenously every 3 weeks or paclitaxel 175 mg/m² intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with MEKINIST and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay.
The median age for randomized patients was 54 years, 54% were male, > 99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both ( < 1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with MEKINIST and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive MEKINIST.
Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with MEKINIST. Table 7 and Figure 1 summarize the PFS results.
Table 7: Investigator-Assessed Progression-Free
Survival and Confirmed Objective Response Results in Trial 1
N = 214
N = 108
|Number of Events (%)||117 (55%)||77 (71%)|
|Progressive Disease||107 (50%)||70 (65%)|
|Death||10 (5%)||7 (6%)|
|Median, months (95% CI)||4.8 (4.3, 4.9)||1.5 (1.4, 2.7)|
|HRa (95% CI)||0.47 (0.34, 0.65)|
|P value (log-rank test)||P < 0.0001|
|Confirmed Tumor Responses|
|Objective Response Rate||22%||8%|
|(95% CI)||(17, 28)||(4, 15)|
|CR, n (%)||4 (2%)||0|
|PR, n (%)||43 (20%)||9 (8%)|
|Duration of Response|
|Median, months (95% CI)||5.5 (4.1, 5.9)||NR (3.5, NR)|
|a Pike estimator.
CI = Confidence interval; CR = Complete response; HR = Hazard ratio; NR = Not reached, PFS = Progression-free survival; PR = Partial response.
Figure 1: Kaplan-Meier Curves of Investigator-Assessed
Progression-Free Survival (ITT population) in Trial 1
In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis.
Trial 2 randomized (1:1:1) patients to MEKINIST (at two different doses) in combination with dabrafenib compared with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive MEKINIST 2 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), MEKINIST 1 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), or dabrafenib 150 mg orally twice daily (n = 54). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive dabrafenib as a single agent were offered MEKINIST 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed disease progression. The major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response.
The median age of patients in Trial 2 was 53 years, 57% were male, > 99% were white, 66% of patients had a pretreatment ECOG performance status of 0, 67% had M1c disease, 54% had a normal LDH at baseline, and 8% had a history of brain metastases. Most patients (81%) had not received prior anti-cancer therapy for unresectable or metastatic disease. All patients had tumor containing BRAF V600E or V600K mutations as determined by local laboratory or centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.
The median duration of follow-up was 14 months. Efficacy outcomes for the arm receiving MEKINIST 2 mg daily in combination with dabrafenib and the arm receiving dabrafenib as a single agent are summarized in Table 8.
Table 8: Investigator-Assessed and Independent Review
Committee-Assessed Response Rates and Response Durations in Trial 2
|Endpoints||MEKINIST plus Dabrafenib
N = 54
N = 54
|Responders (ORR%)||41 (76%)||29 (54%)|
|(95% CI)||(62%, 87%)||(40%, 67%)|
|Duration of Response (months)|
|(95% CI)||(7, 15)||(5, 7)|
|Independent Radiology Review Committee Assessment|
|Responders (ORR%)||31 (57%)||25 (46%)|
|(95% CI)||(43%, 71%)||(33%, 60%)|
|Duration of Response (months)|
|(95% CI)||(7, NR)||(6, NR)|
|CI = Confidence interval; ORR = Confirmed overall response rate; NR = Not reported.|
The ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma. In exploratory subgroup analyses of the patients with retrospectively confirmed BRAF V600E or V600K mutation-positive melanoma using the THxID™-BRAF assay, the ORR results were also similar to the intent-to-treat analysis.30
Lack Of Clinical Activity In Metastatic Melanoma Following BRAF-Inhibitor Therapy
The clinical activity of MEKINIST as a single agent was evaluated in a single-arm, multicenter, international trial (Trial 3) in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received MEKINIST at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity.
The median age was 58 years, 63% were male, all were white, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient in Trial 3 achieved a confirmed partial or complete response as determined by the clinical investigators.
Last reviewed on RxList: 1/22/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Mekinist Information
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