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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 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 MEKINIST 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 heart rate-corrected QT (QTc) prolongation potential of trametinib was assessed in a dedicated study in 32 patients who received placebo on day 1 and MEKINIST 2 mg once daily on days 2-14 followed by MEKINIST 3 mg on day 15. No clinically relevant QTc prolongation was detected in the study.
In clinical trials in patients receiving MEKINIST plus dabrafenib, QTc prolongation > 500 ms occurred in 0.8% (2/264) of patients, and QTc increased by > 60 ms from baseline in 3.8% (10/264) of patients.
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 of MEKINIST, 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 MEKINIST 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 MEKINIST with a high-fat, high-calorie meal decreased trametinib 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 mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and may also be mediated by other hydrolytic enzymes.
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 of trametinib 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, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as parent.
Age, Body Weight, and Gender: Based on a population pharmacokinetic analysis, age, sex, 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 greater than 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 (less than 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.
Effect of CYP Enzymes on Trametinib: Trametinib is not a substrate of CYP enzymes in vitro.
Effect of Trametinib on CYP Substrates: Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at a clinically relevant systemic concentration of 0.04 μM. Trametinib is an inducer of CYP3A in vitro. Based on cross-study comparisons, oral administration of MEKINIST 2 mg once daily with a sensitive CYP3A4 substrate had no clinically important effect on the AUC and Cmax of the sensitive CYP3A4 substrate.
Effect of Transporters on Trametinib: Trametinib is a substrate of P-glycoprotein (P-gp) and bile salt extrusion pump (BSEP). Inhibition of P-gp is unlikely to result in a clinically important increase in trametinib concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1 (OCT1), multidrug resistance protein 2 (MRP2), or multidrug and toxin extrusion 1 (MATE1) in vitro.
Effect of Trametinib on Transporters: Based on in vitro studies, trametinib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT1, OAT3), OCT2, BSEP, MRP2, or MATE1 at a clinically relevant systemic concentration of 0.04 μM.
Effect of Dabrafenib on Trametinib: Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in no change in AUC of trametinib as compared with administration of trametinib.
BRAF V600E Or V600K Mutation-Positive Unresectable Or Metastatic Melanoma
Mekinist As A Single Agent
The safety and efficacy of MEKINIST were evaluated in an international, multicenter, randomized (2:1), open-label, active-controlled trial (Trial 1) in 322 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, greater than 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%), had 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 (less than 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 (95% CI)||22%(17, 28)||8%(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)|
|CI = Confidence interval; HR = Hazard ratio; CR =
Complete response; PR = Partial response; NR = Not reached.
a Pike estimator.
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.
Mekinist With Dabrafenib
The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (Trial 2). Trial 2 compared dabrafenib plus MEKINIST to dabrafenib plus placebo as first-line treatment for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by lactate dehydrogenase (LDH) level (greater than the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).
In Trial 2, 423 patients were randomized to MEKINIST plus dabrafenib (n = 211) or dabrafenib plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, > 99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma.
Trial 2 demonstrated statistically significant improvements in PFS and OS (see Table 8 and Figure 2).
Table 8: Efficacy Results in Trial 2
|Endpoint†||MEKINIST plus dabrafenib
|Dabrafenib plus Placebo
|Progression-Free Survival (PFS)a|
|Number of events (%)||102 (48%)||109 (51%)|
|Median, months (95% CI)||9.3 (7.7, 11.1)||8.8 (5.9, 10.9)|
|HR (95% CI)||0.75 (0.57, 0.99)|
|Number of deaths (%)||99 (47% )||123 (58%)|
|Median, months (95% CI)||25.1 (19.2, NR)||18.7 (15.2, 23.1)|
|HR (95% CI)||0.71 (0.55, 0.92)|
|Overall Response Rate (ORR)b|
|ORR, % (95% CI)||66 (60, 73)||51 (44, 58)|
|P value||< 0.001|
|Median duration of response, months (95% CI)||9.2 (7.4, NR)||10.2 (7.5, NR)|
|† CI = Confidence interval; HR = Hazard ratio; CR =
Complete response; PR = Partial response; NR = Not reached.
a PFS and ORR were assessed by investigator.
b Based on stratified log-rank test
Figure 2: Kaplan Meier Curves of Overall Survival in
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 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 achieved a confirmed partial or complete response as determined by the clinical investigators.
Last reviewed on RxList: 3/22/2016
This monograph has been modified to include the generic and brand name in many instances.
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