In clinical trials with trametinib monotherapy one case of accidental overdose was reported; a single dose of 4 mg. No AEs were reported following this event of trametinib overdose. In clinical trials with the combination of trametinib and dabrafenib 11 patients reported trametinib overdose (4 mg); no SAEs were reported. There is no specific treatment for overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Unopened bottle: 2 years
Opened bottle: 30 days
Not applicable.
Mekinist 0.5 mg film-coated tablets
Tablet core
Mannitol (E421)
Microcrystalline cellulose (E460)
Hypromellose (E464)
Croscarmellose sodium (E468)
Magnesium stearate (E470b)
Sodium laurilsulfate
Colloidal silicon dioxide(E551)
Tablet film-coat
Hypromellose (E464)
Titanium dioxide (E171)
Polyethylene glycol
Iron oxide yellow(E172)
Mekinist 2 mg film-coated tablets
Tablet core
Mannitol (E421)
Microcrystalline cellulose (E460)
Hypromellose (E464)
Croscarmellose sodium (E468)
Magnesium stearate (E470b)
Sodium laurilsulfate
Colloidal silicon dioxide(E551)
Tablet film-coat
Hypromellose (E464)
Titanium dioxide (E171)
Polyethylene glycol
Polysorbate 80 (E433)
Iron oxide red (E172)
Film-coated tablet
Mekinist 0.5 mg film-coated tablets
Yellow, modified oval, biconvex, film-coated tablets, approximately 4.8 x 8.9 mm, with “GS†debossed on one face and “TFC†on the opposing face.
Mekinist 2 mg film-coated tablets
Pink, round, biconvex, film-coated tablets, approximately 7.5 mm, with “GS†debossed on one face and “HMJ†on the opposing face.
Summary of the safety profile
The safety of trametinib monotherapy has been evaluated in the integrated safety population of 329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with trametinib 2 mg once daily. Of these patients, 211 were treated with trametinib for BRAF V600 mutant melanoma in the randomised open label phase III study MEK114267 (METRIC). The most common adverse reactions (incidence >20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform.
The safety of trametinib in combination with dabrafenib has been evaluated in the integrated safety population of 641 patients with BRAF V600 mutant unresectable or metastatic melanoma and advanced NSCLC treated with trametinib 2 mg once daily and dabrafenib 150 mg twice daily. Of these patients, 559 were treated with the combination for BRAF V600 mutant melanoma in two randomised Phase III studies, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), and 82 were treated with the combination for BRAF V600 mutant NSCLC in a multi-cohort, non-randomised Phase II study BRF113928.
The most common adverse reactions (incidence >20%) for trametinib in combination with dabrafenib were: pyrexia, nausea, diarrhoea, fatigue, chills, headache, vomiting, arthralgia, hypertension, rash and cough.
Tabulated summary of adverse reactions
Adverse reactions are listed below by MedDRA body system organ class.
The following convention has been utilised for the classification of frequency:
| Very common Common Uncommon Rare Not known | >1/10 >1/100 to <1/10 >1/1,000 to <1/100 >1/10,000 to <1/1,000 (cannot be estimated from the available data) |
Categories have been assigned based on absolute frequencies in the clinical trial data. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 4 Adverse reactions reported in the integrated safety population of trametinib monotherapy (n=329)
|
System Organ Class |
Frequency (all grades) |
Adverse Reactions |
|
Infections and infestation |
Common |
Folliculitis |
|
Paronychia | ||
|
Cellulitis | ||
|
Rash pustular | ||
|
Blood and lymphatic system disorders |
Common |
Anaemia |
|
Immune system disorders |
Common |
Hypersensitivitya |
|
Metabolism and nutrition disorders |
Common |
Dehydration |
|
Eye disorders |
Common |
Vision blurred |
|
Periorbital oedema | ||
|
Visual impairment | ||
|
Uncommon |
Chorioretinopathy | |
|
Papilloedema | ||
|
Retinal detachment | ||
|
Retinal vein occlusion | ||
|
Cardiac disorders |
Common |
Left ventricular dysfunction |
|
Ejection fraction decreased | ||
|
Bradycardia | ||
|
Uncommon |
Cardiac failure | |
|
Vascular disorders |
Very common |
Hypertension |
|
Haemorrhageb | ||
|
Common |
Lymphoedema | |
|
Respiratory, thoracic and mediastinal disorders |
Very common |
Cough |
|
Dyspnoea | ||
|
Common |
Pneumonitis | |
|
Uncommon |
Interstitial lung disease | |
|
Gastrointestinal disorders |
Very common |
Diarrhoea |
|
Nausea | ||
|
Vomiting | ||
|
Constipation | ||
|
Abdominal pain | ||
|
Dry mouth | ||
|
Common |
Stomatitis | |
|
Uncommon |
Gastrointestinal perforation | |
|
Colitis | ||
|
Skin and subcutaneous disorders |
Very common |
Rash |
|
Dermatitis acneiform | ||
|
Dry skin | ||
|
Pruritus | ||
|
Alopecia | ||
|
Common |
Erythema | |
|
Palmar-plantar erythrodysaesthesia syndrome | ||
|
Skin fissures | ||
|
Skin chapped | ||
|
Musculoskeletal and connective tissue disorders |
Uncommon |
Rhabdomyolysis |
|
General disorders and administration site conditions |
Very common |
Fatigue |
|
Oedema peripheral | ||
|
Pyrexia | ||
|
Common |
Face oedema | |
|
Mucosal inflammation | ||
|
Asthenia | ||
|
Investigations |
Very common |
Aspartate aminotransferase increased |
|
Common |
Alanine aminotransferase increased | |
|
Blood alkaline phosphatase increased | ||
|
Blood creatine phosphokinase increased | ||
|
a May present with symptoms such as fever, rash, increased liver transaminases, and visual disturbances b Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, haematuria, and rectal, haemorrhoidal, gastric, vaginal, conjunctival, intracranial and post procedural haemorrhage. | ||
Table 5 Adverse reactions reported in the integrated safety population of trametinib in combination with dabrafenib (n=641)
|
System Organ Class |
Frequency (all grades) |
Adverse Reactions |
|
Infections and Infestations |
Very common |
Urinary tract infection |
|
Nasopharyngitis | ||
|
Common |
Cellulitis | |
|
Folliculitis | ||
|
Paronychia | ||
|
Rash pustular | ||
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
Common |
Cutaneous squamous cell carcinomaa |
|
Papillomab | ||
|
Seborrhoeic keratosis | ||
|
Uncommon |
New primary melanoma | |
|
Acrochordon (skin tags) | ||
|
Blood and lymphatic system disorders |
Very common |
Neutropenia |
|
Common |
Anaemia | |
|
Thrombocytopenia | ||
|
Leukopenia | ||
|
Immune system disorders |
Uncommon |
Hypersensitivityc |
|
Metabolism and nutrition disorders |
Very common |
Decreased appetite |
|
Common |
Dehydration | |
|
Hyponatraemia | ||
|
Hypophosphataemia | ||
|
Hyperglycaemia | ||
|
Nervous system disorders |
Very common |
Headache |
|
Dizziness | ||
|
Eye disorders |
Common |
Vision blurred |
|
Visual impairment | ||
|
Uncommon |
Chorioretinopathy | |
|
Uveitis | ||
|
Retinal detachment | ||
|
Periorbital oedema | ||
|
Cardiac disorders |
Common |
Ejection fraction decreased |
|
Uncommon |
Bradycardia | |
|
Unknown |
Myocarditis | |
|
Vascular disorders |
Very common |
Hypertension |
|
Haemorrhaged | ||
|
Common |
Hypotension | |
|
Lymphoedema | ||
|
Respiratory, thoracic and mediastinal disorders |
Very common |
Cough |
|
Common |
Dyspnoea | |
|
Pneumonitis | ||
|
Gastrointestinal disorders |
Very common |
Abdominal pain |
|
Constipation | ||
|
Diarrhoea | ||
|
Nausea | ||
|
Vomiting | ||
|
Common |
Dry mouth | |
|
Stomatitis | ||
|
Uncommon |
Pancreatitis | |
|
Gastrointestinal perforation | ||
|
Colitis | ||
|
Skin and subcutaneous disorders |
Very common |
Dry skin |
|
Pruritus | ||
|
Rash | ||
|
Erythema | ||
|
Common |
Dermatitis acneiform | |
|
Actinic keratosis | ||
|
Night sweats | ||
|
Hyperkeratosis | ||
|
Alopecia | ||
|
Palmar-plantar erythrodysaesthesia syndrome | ||
|
Skin lesion | ||
|
Hyperhidrosis | ||
|
Panniculitis | ||
|
Skin fissures | ||
|
Photosensitivity reaction | ||
|
Musculoskeletal and connective tissue disorders |
Very common |
Arthralgia |
|
Myalgia | ||
|
Pain in extremity | ||
|
Muscle spasms | ||
|
Renal and urinary disorders |
Common |
Renal failure |
|
Uncommon |
Nephritis | |
|
General disorders and administration site conditions |
Very common |
Fatigue |
|
Chills | ||
|
Asthenia | ||
|
Oedema peripheral | ||
|
Pyrexia | ||
|
Common |
Mucosal inflammation | |
|
Influenza-like illness | ||
|
Face oedema | ||
|
Investigations |
Very common |
Alanine aminotransferase increased |
|
Aspartate aminotransferase increased | ||
|
Common |
Blood alkaline phosphatase increased | |
|
Gamma-glutamyltransferase increased | ||
|
Blood creatine phosphokinase increased | ||
|
a cu SCC: SCC, SCC of the skin, SCC in situ (Bowen's disease) and keratoacanthoma b Papilloma, skin papilloma c Includes drug hypersensitivity d Bleeding from various sites, including intracranial bleeding and fatal bleeding | ||
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Description of selected adverse reactions
New malignancies
New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib. Please refer to the dabrafenib SmPC.
Haemorrhage
Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages occurred in patients taking trametinib as monotherapy and in combination with dabrafenib. The majority of bleeding events were mild. Fatal intracranial haemorrhages occurred in the integrated safety population of trametinib in combination with dabrafenib in 1% (8/641) of patients. The median time to onset of the first occurrence of haemorrhagic events for the combination of trametinib and dabrafenib was 94 days in the melanoma Phase III studies and 75 days in the NSCLC study for the patients who had received prior anti-cancer therapy.
The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinically indicated.
LVEF reduction/Left ventricular dysfunction
Trametinib has been reported to decrease LVEF when used as monotherapy or in combination with dabrafenib. In clinical trials, the median time to first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 to 5 months. In the integrated safety population of trametinib in combination with dabrafenib, decreased LVEF has been reported in 8% (54/641) of patients with most cases being asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with trametinib. Trametinib should be used with caution in patients with conditions that could impair left ventricular function.
Pyrexia
Pyrexia has been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib; however, the incidence and severity of pyrexia are increased with the combination therapy.8 of the dabrafenib SmPC.
Hepatic events
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib. Of the hepatic AEs, increased ALT and AST were the most common events and the majority were either Grade 1 or 2. For trametinib monotherapy, more than 90% of these liver events occurred within the first 6 months of treatment. Liver events were detected in clinical trials with monitoring every four weeks. It is recommended that patients receiving treatment with trametinib monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated.
Hypertension
Elevations in blood pressure have been reported in association with trametinib as monotherapy and in combination with dabrafenib, in patients with or without pre-existing hypertension. Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.
Interstitial lung disease (ILD)/Pneumonitis
Patients treated with trametinib or combination with dabrafenib may develop ILD or pneumonitis. Trametinib should be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. For patients diagnosed with treatment-related ILD or pneumonitis trametinib should be permanently discontinued.
Visual impairment
Disorders associated with visual disturbances, including RPED and RVO, have been observed with trametinib. Symptoms such as blurred vision, decreased acuity, and other visual disturbances have been reported in the clinical trials with trametinib.
Rash
Rash has been observed in about 60% of patients when given as monotherapy and in about 25% of patients in trametinib and dabrafenib combination studies in the integrated safety population. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.
Rhabdomyolysis
Rhabdomyolysis has been reported in patients taking trametinib alone or in combination with dabrafenib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated.
Pancreatitis
Pancreatitis has been reported with dabrafenib in combination with trametinib. Please see the dabrafenib SmPC.
Renal failure
Renal failure has been reported with dabrafenib in combination with trametinib. Please see the dabrafenib SmPC.
Special populations
Elderly
In the phase III study with trametinib in patients with unresectable or metastatic melanoma (n=211), 49 patients (23%) were >65 years of age, and 9 patients (4%) were >75 years of age. The proportion of subjects experiencing adverse events (AE) and serious adverse events (SAE) was similar in the subjects aged <65 years and those aged >65 years. Patients >65 years were more likely to experience AEs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
In the integrated safety population of trametinib in combination with dabrafenib (n=641) 180 patients (28%) were >65 years of age; 50 patients (8%) were >75 years of age. The proportion of patients experiencing AEs was similar in those aged <65 years and those aged >65 years in all studies. Patients >65 years were more likely to experience SAEs and AEs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
Renal impairment
No dosage adjustment is required in patients with mild or moderate renal impairment. Trametinib should be used with caution in patients with severe renal impairment.
Hepatic impairment
No dosage adjustment is required in patients with mild hepatic impairment. Trametinib should be used with caution in patients with moderate or severe hepatic impairment
Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and micronuclei in the bone marrow of rats.
Trametinib may impair female fertility in humans, as in repeat-dose studies, increases in cystic follicles and decreases in corpora lutea were observed in female rats at exposures below the human clinical exposure based on AUC.
Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks of female sexual maturation (vaginal opening and increased incidence of prominent terminal end buds within the mammary gland) and slight hypertrophy of the surface epithelium of the uterus were observed. All of these effects were reversible following an off-treatment period and attributable to pharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed in male reproductive tissues.
In embryo-foetal developmental toxicity studies in rats and rabbits, trametinib induced maternal and developmental toxicity. In rats decreased foetal weights and increased post-implantation loss were seen at exposures below or slightly above the clinical exposures based on AUC. In an embryo-foetal developmental toxicity study with rabbits, decreased foetal body weight, increased abortions, increased incidence of incomplete ossification and skeletal malformations were seen at sub-clinical exposures based on AUC).
In repeat-dose studies the effects seen after trametinib exposure are found mainly in the skin, gastrointestinal tract, haematological system, bone and liver. Most of the findings are reversible after drug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen after 8 weeks at >0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on AUC).
In mice, lower heart rate, heart weight and left ventricular function were observed without cardiac histopathology after 3 weeks at >0.25 mg/kg/day trametinib (approximately 3 times human clinical exposure based on AUC) for up to 3 weeks. In adult rats, mineralisation of multiple organs was associated with increased serum phosphorus and was closely associated with necrosis in heart, liver and kidney and haemorrhage in the lung at exposures comparable to the human clinical exposure. In rats, hypertrophy of the physis and increased bone turnover were observed, but the physeal hypertrophy is not expected to be clinically relevant for adult humans. In rats and dogs given trametinib at or below clinical exposures, bone marrow necrosis, lymphoid atrophy in thymus and GALT and lymphoid necrosis in lymph nodes, spleen and thymus were observed, which have the potential to impair immune function. In juvenile rats, increased heart weight with no histopathology was observed at 0.35 mg/kg/day (approximately twice the adult human clinical exposure based on AUC).
Trametinib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay at significantly higher concentrations than clinical exposures (IC50 at 2.92 µg/ml, >130 times the clinical exposure based on Cmax), indicating that there is low risk for phototoxicity to patients taking trametinib.
Combination with dabrafenib
In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs of gastro-intestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lower exposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as in comparable monotherapy studies.
Melanoma
Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy.
Non-small cell lung cancer (NSCLC)
Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation.
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE25
Mechanism of action
Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity. Trametinib inhibits growth of BRAF V600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.
Combination with dabrafenib
Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of trametinib with dabrafenib has shown anti-tumour activity in BRAF V600 mutation positive melanoma cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation positive melanoma xenografts.
Determination of BRAF mutation status
Before taking trametinib or the combination with dabrafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test.
In clinical trials, central testing for BRAF V600 mutation using a BRAF mutation assay was conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with a validated polymerase chain reaction (PCR) assay developed by Response Genetics Inc. The assay was specifically designed to differentiate between the V600E and V600K mutations. Only patients with BRAF V600E or V600K mutation positive tumours were eligible for study participation.
Subsequently, all patient samples were re-tested using the CE-marked bioMerieux (bMx) THxID BRAF validated assay. The bMx THxID BRAF assay is an allele-specific PCR performed on DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600K mutations with high sensitivity (down to 5% V600E and V600K sequence in a background of wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with retrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less common BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the specimens from the non-clinical and clinical studies (n=876) that were mutation positive by the THxID BRAF assay and subsequently were sequenced using the reference method, the specificity of the assay was 94%.
Pharmacodynamic effects
Trametinib suppressed levels of phosphorylated ERK in BRAF mutant melanoma tumour cell lines and melanoma xenograft models.
In patients with BRAF and NRAS mutation positive melanoma, administration of trametinib resulted in dose-dependent changes in tumour biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). The mean trametinib concentrations observed following repeat dose administration of 2 mg once daily exceeds the preclinical target concentration over the 24-hr dosing interval, thereby providing sustained inhibition of the MEK pathway.
Clinical efficacy and safety
Melanoma
In the clinical studies only patients with cutaneous melanoma were studied. Efficacy in patients with ocular or mucosal melanoma has not been assessed.
- Trametinib in combination with dabrafenib
Treatment naïve patients
The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation was studied in two Phase III studies and one supportive Phase I/II study.
MEK115306 (COMBI-d):
MEK115306 was a Phase III, randomised, double-blinded study comparing the combination of dabrafenib and trametinib to dabrafenib and placebo in first-line therapy for subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study was progression-free survival (PFS), with a key secondary endpoint of overall survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).
A total of 423 subjects were randomised 1:1 to either combination (N=211) or dabrafenib (N=212). Most subjects were Caucasian (>99%) and male (53%), with a median age of 56 years (28% were >65 years). The majority of subjects had Stage IVM1c disease (67%). Most subjects had LDH ≤ULN (65%), Eastern Cooperative Oncology Group (ECOG) performance status of 0 (72%), and visceral disease (73%) at baseline. The majority of subjects had a BRAF V600E mutation (85%). Subjects with brain metastases were not included in the trial.
The final OS analysis (12 January 2015) demonstrated a statistically significant improvement in OS for the combination compared with dabrafenib monotherapy (Figure 1). The 1-year (74%) and 2-year (51%) OS estimates for the combination arm were greater than those for dabrafenib monotherapy (68% and 42% respectively).
An updated OS analysis (15 February 2016) demonstrated an improvement in OS for the combination compared with dabrafenib monotherapy. The 3-year OS estimate for the combination arm was greater than for dabrafenib monotherapy (44% versus 32%, respectively). The median OS for the combination arm was approximately 8 months longer than the median OS for dabrafenib monotherapy (26.7 months versus 18.7 months). These data also demonstrated a reduction in the risk of death (HR=0.75, 95% CI: 0.58, 0.96) which was consistent with the primary OS analysis.
Figure 1 Kaplan-Meier overall survival curves for Study MEK115306 (ITT population)
Statistically significant improvements were observed for the primary endpoint of PFS and secondary endpoint of overall response rate (ORR). A longer duration of response (DoR) is also observed (Table 6).
Table 6 Efficacy results for Study MEK115306 (COMBI-d)
|
Endpoint |
Dabrafenib + Trametinib (N=211) |
Dabrafenib + Placebo (N=212) |
Dabrafenib + Trametinib (N=211) |
Dabrafenib + Placebo (N=212) |
|
Data cut-off date |
26 August 2013 |
12 January 2015 | ||
|
PFSa | ||||
|
Progressive disease or death, n (%) |
102 (48) |
109 (51) |
139 (66) |
162 (76) |
|
Median PFS (months) (95% CI) |
9.3 (7.7, 11.1) |
8.8 (5.9, 10.9) |
11.0 (8.0, 13.9) |
8.8 (5.9, 9.3) |
|
Hazard Ratio (95% CI) |
0.75 (0.57, 0.99) |
0.67 (0.53, 0.84) | ||
|
P value |
0.035 |
<0.001 | ||
|
ORRb (95% CI) |
67 (59.9, 73.0) |
51 (44.5, 58.4) |
69 (61.8,74.8) |
53 (46.3, 60.2) |
|
ORR difference (95% CI) |
15e (5.9, 24.5) |
15e (6.0, 24.5) | ||
|
P value |
0.0015 |
0.0014 | ||
|
DoRc (months) Median (95% CI) |
9.2d (7.4, NR) |
10.2d (7.5, NR) |
12.9 (9.4,19.5) |
10.6 (9.1, 13.8) |
|
a - Progression-free survival (investigator assessed) b - Overall Response Rate = Complete Response + Partial Response c - Duration of response d - At the time of the reporting the majority (>59%) of investigator-assessed responses were still ongoing e - ORR difference calculated based on the ORR result not rounded NR = Not reached | ||||
MEK116513 (COMBI-v):
Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing dabrafenib and trametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of the study was OS with a key secondary endpoint of PFS. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).
A total of 704 subjects were randomised 1:1 to either combination or vemurafenib. Most subjects were Caucasian (>96%) and male (55%), with a median age of 55 years (24% were >65 years). The majority of subjects had Stage IV M1c disease (61% overall). Most subjects had LDH ≤ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at baseline. Overall, 54% of subjects had <3 disease sites at baseline. The majority of subjects had BRAF V600E mutation-positive melanoma (89%). Subjects with brain metastases were not included in the trial.
The updated OS analysis (13 March 2015) demonstrated a statistically significant improvement in OS for the combination compared with vemurafenib monotherapy (Figure 2). The 1-year OS estimate was 72% for combination therapy and 65% for vemurafenib.
An updated OS analysis (15 July 2016) demonstrated improvement in OS for the combination compared with vemurafenib monotherapy. The 3-year OS estimate was 45% for combination therapy and 31% for vemurafenib. The median OS for the combination arm was approximately 8 months longer than the median OS for vemurafenib monotherapy (26.1 months versus 17.8 months). These data also demonstrated a reduction in the risk of death (HR=0.68, 95% CI: 0.56, 0.83) which was consistent with the primary OS analysis.
Figure 2 Kaplan-Meier curves Updated OS analysis for Study MEK116513
Statistically significant improvements are observed for the secondary endpoints of PFS and ORR. A longer DoR is also observed (Table 7).
Table 7 Efficacy results for Study MEK116513 (COMBI-v)
|
Endpoint |
Dabrafenib + Trametinib (N=352) |
Vemurafenib (N=352) |
|
PFS | ||
|
Progressive disease or death, n (%) |
166 (47) |
217 (62) |
|
Median PFS (months) (95% CI) |
11.4 (9.9, 14.9) |
7.3 (5.8, 7.8) |
|
Hazard Ratio (95% CI) |
0.56 (0.46, 0.69) | |
|
P value |
<0.001 | |
|
ORR (95% CI) |
226 (64) (59.1, 69.4) |
180 (51) (46.1, 56.8) |
|
ORR difference (95% CI) |
13 (5.7, 20.2) | |
|
P value |
0.0005 | |
|
DoR (months) Median (95% CI) |
13.8 (11.0, NR) |
7.5 (7.3, 9.3) |
Prior BRAF inhibitor therapy
There are limited data in patients taking the combination of trametinib with dabrafenib who have progressed on a prior BRAF inhibitor.
Part B of study BRF113220 included a cohort of 26 patients that had progressed on a BRAF inhibitor. The trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination demonstrated limited clinical activity in patients who had progressed on a BRAF inhibitor. The investigator-assessed confirmed response rate was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI: 1.9, 5.2). Similar results were seen in the 45 patients who crossed over from dabrafenib monotherapy to the trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination in Part C of this study. In these patients a 13% (95% CI: 5.0, 27.0) confirmed response rate was observed with a median PFS of 3.6 months (95% CI: 2, 4).
- Trametinib monotherapy
Treatment naïve patients
The efficacy and safety of trametinib in patients with BRAF mutant melanoma (V600E and V600K) were evaluated in a randomised open-label Phase III study (MEK114267 [METRIC]). Measurement of patients' BRAF V600 mutation status was required.
Patients (N=322) who were treatment naïve or may have received one prior chemotherapy treatment in the metastatic setting [Intent to Treat (ITT) population] were randomised 2:1 to receive trametinib 2 mg once daily or chemotherapy (dacarbazine 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Treatment for all patients continued until disease progression, death or withdrawal.
The primary endpoint of the study was to evaluate the efficacy of trametinib compared to chemotherapy with respect to PFS in patients with advanced/metastatic BRAF V600E/K mutation-positive melanoma without a prior history of brain metastases (N=273) which is considered the primary efficacy population. The secondary endpoints were PFS in the ITT population and OS, ORR, and DoR in the primary efficacy population and ITT population. Patients in the chemotherapy arm were allowed to cross-over to the trametinib arm after independent confirmation of progression. Of the patients with confirmed disease progression in the chemotherapy arm, a total of 51 (47%) crossed over to receive trametinib.
Baseline characteristics were balanced between treatment groups in the primary efficacy population and the ITT population. In the ITT population, 54% of patients were male and all were Caucasian. The median age was 54 years (22% were >65 years); all patients had an ECOG performance score of 0 or 1; and 3 % had history of brain metastases. Most patients (87%) in the ITT population had BRAF V600E mutation and 12% of patients had BRAF V600K. Most patients (66%) received no prior chemotherapy for advanced or metastatic disease.
The efficacy results in the primary efficacy population were consistent with those in the ITT population; therefore, only the efficacy data for the ITT population are presented in Table 8. Kaplan-Meier curves of investigator assessed OS (post-hoc analysis 20 May 2013) is presented in Figure 3.
Table 8 Investigator assessed efficacy results (ITT population)
|
Endpoint |
Trametinib |
Chemotherapya |
|
Progression-Free Survival |
(N=214) |
(N=108) |
|
Median PFS (months) (95% CI) |
4.8 (4.3, 4.9) |
1.5 (1.4, 2.7) |
|
Hazard Ratio (95% CI) P value |
0.45 (0.33, 0.63) <0.0001 | |
|
Overall Response Rate (%) |
22 |
8 |
|
ITT = Intent to Treat; PFS = Progression-free survival; CI = confidence interval. a Chemotherapy included patients on dacarbazine (DTIC) 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks. | ||
The PFS result was consistent in the subgroup of patients with V600K mutation positive melanoma (HR=0.50; [95% CI: 0.18, 1.35], p=0.0788).
An additional OS analysis was undertaken based upon the 20 May 2013 data cut, see Table 9.
For October 2011, 47% of subjects had crossed over, while for May 2013, 65% of subjects had crossed over.
Table 9 Survival data from the primary and post-hoc analyses
|
Cut-off dates |
Treatment |
Number of deaths (%) |
Median months OS (95% CI) |
Hazard ratio (95% CI) |
Percent survival at 12 months (95% CI) |
|
October 26, 2011 |
Chemotherapy (n=108) |
29 (27) |
NR |
0.54 (0.32, 0.92) |
NR |
|
Trametinib (n=214) |
35 (16) |
NR |
NR | ||
|
May 20, 2013 |
Chemotherapy (n=108) |
67 (62) |
11.3 (7.2, 14.8) |
0.78 (0.57, 1.06) |
50 (39,59) |
|
Trametinib (n=214) |
137 (64) |
15.6 (14.0, 17.4) |
61(54, 67) | ||
|
NR=not reached | |||||
Figure 3 Kaplan-Meier curves of overall survival (OS -ad hoc analysis 20 May 2013)
Prior BRAF inhibitor therapy
In a single-arm Phase II study, designed to evaluate the objective response rate, safety, and pharmacokinetics following dosing of trametinib at 2 mg once daily in patients with BRAF V600E, V600K, or V600D mutation-positive metastatic melanoma (MEK113583), two separate cohorts were enrolled: Cohort A: patients with prior treatment with a BRAF inhibitor either with or without other prior therapy, Cohort B: patients with at least 1 prior chemotherapy or immunotherapy, without prior treatment with a BRAF inhibitor.
In Cohort A of this study, trametinib did not demonstrate clinical activity in patients who had progressed on a prior BRAF inhibitor therapy.
Non-small cell lung cancer
Study BRF113928
The efficacy and safety of trametinib in combination with dabrafenib was studied in a Phase II, three-cohort, multicentre, non-randomised and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled. The primary endpoint was ORR using the 'Response Evaluation Criteria In Solid Tumors' (RECIST 1.1) assessed by the investigator. Secondary endpoints included DoR, PFS, OS, safety and population pharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review Committee (IRC) as a sensitivity analysis.
Cohorts were enrolled sequentially:
- Cohort A: Monotherapy (dabrafenib 150 mg twice daily), 84 patients enrolled. 78 patients had previous systemic treatment for their metastatic disease.
- Cohort B: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily), 59 patients enrolled. 57 patients had 1-3 lines of previous systemic treatment for their metastatic disease. 2 patients had no previous systemic treatment and were included in the analysis for patients enrolled in Cohort C.
- Cohort C: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily), 34 patients. All patients received study medication as first-line treatment for metastatic disease.
Among the total of 93 patients who were enrolled in the combination therapy cohorts B and C, most patients were Caucasian (>90%), and similar female versus male (54% versus 46%), with a median age of 64 years in second line or higher patients and 68 years in the first line patients. Most patients (94%) enrolled in the combination therapy treated cohorts had an ECOG performance status of 0 or 1. 26 (28%) had never smoked. The majority of patients had a non-squamous histology. In the previously treated population, 38 patients (67%) had one line of systemic anti-cancer therapy for metastatic disease.
For the primary endpoint of investigator-assessed ORR, the ORR in the first line population was 61.1% (95% CI, 43.5%, 76.9%) and in the previously treated population was 66.7% (95% CI, 52.9%, 78.6%). These met the statistical significance to reject the null hypothesis that the ORR of dabrafenib in combination with trametinib for this NSCLC population was less than or equal to 30%. The ORR results assessed by IRC were consistent with the investigator assessment. The response was durable with median DoR in the previously treated population reaching 9.8 months (95% CI, 6.9, 16.0) by investigator assessment. In the first line population, 68% of patients had not progressed after 9 months. The median DoR and PFS were not yet estimable (Table 10).
Table 10 Summary of efficacy in the combination treatment cohorts based on investigator and independent radiology review
|
Endpoint |
Analysis |
Combination 1st Line N=361 |
Combination 2nd Line Plus N=571 |
|
Overall confirmed response n (%) (95% CI) |
By Investigator
By IRC |
22 (61.1%) (43.5, 76.9) 22 (61.1%) (43.5, 76.9) |
38 (66.7%) (52.9, 78.6) 36 (63.2%) (49.3, 75.6) |
|
Median DoR Months (95% CI) |
By Investigator By IRC |
NE2 (8.3, NE) NE (6.9, NE) |
9.8 (6.9, 16.0) 12.6 (5.8, NE) |
|
Median PFS Months (95% CI) |
By Investigator By IRC |
-3 -3 |
10.2 (6.9, 16.7) 8.6 (5.2, 16.8) |
|
Median OS Months (95% CI) |
- |
24.6 (11.7, NE)4 |
18.2 (14.3, NE) |
|
1 Data cut-off: 8th August 2016 2 NE: Not Evaluable 3 Median PFS currently not estimable 4 Event rate for OS calculation was 28% and hence the defined median value still needs to mature | |||
Paediatric population
Absorption
Trametinib is absorbed orally with median time to achieve peak concentrations of 1.5 hours post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72% relative to an intravenous (IV) microdose. The increase in exposure (Cmax and AUC) was dose-proportional following repeat dosing. Following administration of 2 mg once daily, steady-state geometric mean Cmax, AUC(0-) and predose concentration were 22.2 ng/ml, 370 ng*hr/ml and 12.1 ng/ml, respectively with a low peak:trough ratio (1.8). Inter-subject variability at steady state was low (<28%).
Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady-state was achieved by Day 15.
Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a 70% and 10% decrease in Cmax and AUC, respectively compared to fasted conditions.
Distribution
Binding of trametinib to human plasma proteins is 97.4%. Trametinib has a volume of distribution of approximately 1200 L determined following administration of a 5 μg intravenous microdose.
Biotransformation
In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly via deacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite was further metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway of metabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with possible contributions by other hydrolytic enzymes.
Following single and repeated doses of trametinib, trametinib as parent is the main circulating component in plasma.
Elimination
Mean terminal half-life is 127 hours (5.3 days) after single dose administration. Trametinib plasma IV clearance is 3.21 L/hr.
Total dose recovery was low after a 10-day collection period (<50%) following administration of a single oral dose of radiolabelled trametinib as a solution, due to the long elimination half-life. Drug-related material was excreted predominantly in the faeces (>80% of recovered radioactivity) and to a minor extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in urine.
Special patient populations
Hepatic impairment
A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels (based on National Cancer Institute [NCI] classification) do not significantly affect trametinib oral clearance. No data are available in patients with moderate or severe hepatic impairment. As metabolism and biliary excretion are the primary routes of elimination of trametinib, administration of trametinib should be undertaken with caution in patients with moderate to severe hepatic impairment.
Renal impairment
Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics given the low renal excretion of trametinib. The pharmacokinetics of trametinib were characterised in 223 patients enrolled in clinical trials with trametinib who had mild renal impairment and 35 patients with moderate renal impairment using a population pharmacokinetic analysis. Mild and moderate renal impairment had no effect on trametinib exposure (<6% for either group). No data are available in patients with severe renal impairment.
Elderly
Based on the population pharmacokinetics analysis (range 19 to 92 years), age had no relevant clinical effect on trametinib pharmacokinetics. Safety data in patients >75 years is limited.
Race
There are insufficient data to evaluate the potential effect of race on trametinib pharmacokinetics as clinical experience is limited to Caucasians.
Paediatric population
No studies have been conducted to investigate the pharmacokinetics of trametinib in paediatric patients.
Body weight and gender
Based on a population pharmacokinetic analysis, gender and body weight were found to influence trametinib oral clearance. Although smaller female subjects are predicted to have higher exposure than heavier male subjects, these differences are unlikely to be clinically relevant and no dosage adjustment is warranted.
Medicinal product interactions
Effects of trametinib on drug-metabolising enzymes and transporters: In vitro and in vivo data suggest that trametinib is unlikely to affect the pharmacokinetics of other medicinal products. Based on in vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9 and CYP2C19, an inducer of CYP3A4 and an inhibitor of the transporters OAT1, OAT3, OCT2, MATE1, OATP1B1, OATP1B3, Pgp and BCRP. However, based on the low dose and low clinical systemic exposure relative to the in vitro potency of inhibition or induction values, trametinib is not considered to be an in vivo inhibitor or inducer of these enzymes or transporters, although transient inhibition of BCRP substrates in the gut may occur.
Effects of other drugs on trametinib: In vivo and in vitro data suggest that the pharmacokinetics of trametinib are unlikely to be affected by other medicinal products. Trametinib is not a substrate of CYP enzymes or of the transporters BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, and MATE1. Trametinib is an in vitro substrate of BSEP and the efflux transporter P-gp. Although trametinib exposure is unlikely to be affected by inhibition of BSEP, increased levels of trametinib upon strong inhibition of hepatic P-gp cannot be excluded.
12 April 2018
Mekinist® 0.5 mg film-coated tablets
Mekinist® 2 mg film-coated tablets
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland
Store in a refrigerator (2°C to 8°C).
Store in the original package in order to protect from light and moisture.
Keep the bottle tightly closed.
Once opened, the bottle may be stored for 30 days at not more than 30°C.
High-density polyethylene (HDPE) bottle with child resistant polypropylene closure. The bottle contains a desiccant.
Pack sizes: One bottle contains either 7 or 30 tablets.
Not all pack sizes may be marketed.
Mekinist 0.5 mg film-coated tablets
EU/1/14/931/001
EU/1/14/931/002
Mekinist 2 mg film-coated tablets
EU/1/14/931/005
EU/1/14/931/006
Women of childbearing potential/Contraception in females
Advise female patients of reproductive potential to use highly effective contraception during treatment with trametinib and for 4 months after treatment.
It is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.
Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternative method of contraception, such as a barrier method, should be used when trametinib is used in combination with dabrafenib. Refer to the dabrafenib SmPC for further information.
Pregnancy
There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studies have shown reproductive toxicity. Trametinib should not be administered to pregnant women or nursing mothers. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, the patient should be informed of the potential hazard to the foetus.
Breast-feeding
It is not known whether trametinib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding infant cannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue trametinib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data in humans for trametinib as monotherapy or in combination with dabrafenib. In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs. Trametinib may impair fertility in humans.
Men taking trametinib in combination with dabrafenib
Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Refer to the dabrafenib SmPC for further information.
Mekinist 0.5 mg film-coated tablets
Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib.
Mekinist 2 mg film-coated tablets
Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib.
When trametinib is given in combination with dabrafenib, the SmPC of dabrafenib must be consulted prior to initiation of treatment. For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib SmPC.
BRAF V600 testing
The efficacy and safety of trametinib have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation.
Trametinib monotherapy compared to BRAF inhibitors
Trametinib monotherapy has not been compared with a BRAF inhibitor in a clinical study in patients with BRAF V600 mutation positive unresectable or metastatic melanoma. Based on cross-study comparisons, overall survival and progression-free survival data appear to show similar effectiveness between trametinib and BRAF inhibitors; however, overall response rates were lower in patients treated with trametinib than those reported in patients treated with BRAF inhibitors.
Trametinib in combination with dabrafenib in patients with melanoma who have progressed on a BRAF inhibitor
There are limited data in patients taking the combination of trametinib with dabrafenib who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients. Therefore other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.
Trametinib in combination with dabrafenib in patients with brain metastases
The safety and efficacy of the combination of trametinib and dabrafenib have not been evaluated in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain.
New malignancies
New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib.
Cutaneous squamous cell carcinoma (cuSCC)
Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with trametinib in combination with dabrafenib.).
New primary melanoma
New primary melanoma was reported in patients receiving trametinib in combination with dabrafenib.).
Non-cutaneous malignancy
Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present.). No dose modification of trametinib is required for RAS mutation positive malignancies when taken in combination with dabrafenib.
Haemorrhage
Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, occurred in patients taking trametinib as monotherapy and in combination with dabrafenib. The potential for these events in patients with unstable and/or symptomatic brain metastases or low platelets (<75,000) is not established as patients with these conditions were excluded from clinical trials. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should be treated as clinically indicated.
LVEF reduction/Left ventricular dysfunction
Trametinib has been reported to decrease LVEF, when used as monotherapy or in combination with dabrafenib. In clinical trials, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 and 5 months.
Trametinib should be used with caution in patients with impaired left ventricular function.).
In patients receiving trametinib in combination with dabrafenib, there have been occasional reports of acute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed when stopping treatment. Physicians should be alert to the possibility of myocarditis in patients who develop new or worsening cardiac signs or symptoms.
Pyrexia
Fever has been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib.). In patients receiving trametinib in combination with dabrafenib, pyrexia may be accompanied by severe rigors, dehydration, and hypotension which in some cases can lead to acute renal insufficiency.
) for dose modifications for dabrafenib. No dose modification of trametinib is required when taken in combination with dabrafenib.Hypertension
Elevations in blood pressure have been reported in association with trametinib as monotherapy and in combination with dabrafenib, in patients with or without pre-existing hypertension. Blood pressure should be measured at baseline and monitored during treatment with trametinib, with control of hypertension by standard therapy as appropriate.
Interstitial lung disease (ILD)/Pneumonitis
In a Phase III trial, 2.4% (5/211) of patients treated with trametinib monotherapy developed ILD or pneumonitis; all five patients required hospitalisation. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). In studies MEK115306 and MEK116513 <1% (2/209) and 1 % (4/350), respectively, of patients treated with trametinib in combination with dabrafenib developed pneumonitis or ILD.
Trametinib should be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Trametinib should be permanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis. If trametinib is being used in combination with dabrafenib then therapy with dabrafenib may be continued at the same dose.
Visual impairment
Disorders associated with visual disturbance, including RPED and RVO, may occur with trametinib as monotherapy and in combination with dabrafenib. Symptoms such as blurred vision, decreased acuity, and other visual phenomena have been reported in the clinical trials with trametinib. In clinical trials uveitis and iridocyclitis have also been reported in patients treated with trametinib in combination with dabrafenib.
Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in subjects with predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes, has not been established.
If patients report new visual disturbances, such as diminished central vision, blurred vision or loss of vision at any time while on trametinib therapy, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued. No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.
Rash
Rash has been observed in about 60% of patients in trametinib monotherapy studies and in about 25% of patients in trametinib and dabrafenib combination studies MEK115306 and MEK116513. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.
Rhabdomyolysis
Rhabdomyolysis has been reported in patients taking trametinib as monotherapy or in combination with dabrafenib. In some cases, patients were able to continue trametinib. In more severe cases hospitalisation, interruption or permanent discontinuation of trametinib or trametinib and dabrafenib combination was required. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated.
Renal failure
Renal failure has been identified in patients treated with trametinib in combination with dabrafenib in clinical studies.).
Pancreatitis
Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib in clinical studies.).
Hepatic events
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib. It is recommended that patients receiving treatment with trametinib monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated.
Hepatic impairment
As metabolism and biliary excretion are the primary routes of elimination of trametinib, administration of trametinib should be undertaken with caution in patients with moderate to severe hepatic impairment.
Deep vein thrombosis (DVT)/Pulmonary embolism (PE)
Pulmonary embolism or deep vein thrombosis can occur when trametinib is used as monotherapy or in combination with dabrafenib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue trametinib and dabrafenib for life-threatening pulmonary embolism.
Gastrointestinal disorders
Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking trametinib as monotherapy and in combination with dabrafenib. Treatment with trametinib monotherapy or in combination with dabrafenib should be used with caution in patients with risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognised risk of gastrointestinal perforation.
Trametinib has minor influence on the ability to drive or use machines. The clinical status of the patient and the adverse reaction profile should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills. Patients should be made aware of potential for fatigue, dizziness or eye problems that might affect these activities.
Treatment with trametinib should only be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products.
Before taking trametinib, patients must have confirmation of BRAF V600 mutation using a validated test.
Posology
The recommended dose of trametinib, either used as monotherapy or in combination with dabrafenib, is 2 mg once daily. The recommended dose of dabrafenib, when used in combination with trametinib, is 150 mg twice daily.
Duration of treatment
It is recommended that patients continue treatment with trametinib until patients no longer derive benefit or the development of unacceptable toxicity.
Missed doses
If a dose of trametinib is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.
If a dose of dabrafenib is missed, when trametinib is given in combination with dabrafenib, the dose of dabrafenib should only be taken if it is more than 6 hours until the next scheduled dose.
Dose modification
The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation (see Tables 1 and 2).
Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see dabrafenib SmPC for further details).
Table 1 Recommended dose level reductions
|
Dose level |
Trametinib dose Used as monotherapy or in combination with dabrafenib |
Dabrafenib dose* Only when used in combination with trametinib |
|
Starting dose |
2 mg once daily |
150 mg twice daily |
|
1st dose reduction |
1.5 mg once daily |
100 mg twice daily |
|
2nd dose reduction |
1 mg once daily |
75 mg twice daily |
|
3rd dose reduction (combination only) |
1 mg once daily |
50 mg twice daily |
|
Dose adjustment for trametinib below 1 mg once daily is not recommended, whether used as monotherapy or in combination with dabrafenib. Dose adjustment for dabrafenib below 50 mg twice daily is not recommended when used in combination with trametinib. | ||
|
*Please refer to the dabrafenib SmPC, Posology and method of administration, for dosing instructions for treatment with dabrafenib monotherapy. | ||
Table 2 Dose modification schedule based on the grade of any Adverse Events (AE)
|
Grade (CTC-AE)* |
Recommended trametinib dose modifications Used as monotherapy or in combination with dabrafenib |
|
Grade 1 or Grade 2 (Tolerable) |
Continue treatment and monitor as clinically indicated. |
|
Grade 2 (Intolerable) or Grade 3 |
Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose level when resuming therapy. |
|
Grade 4 |
Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy. |
|
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE) | |
When an individual's adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. The trametinib dose should not exceed 2 mg once daily.
If treatment-related toxicities occur when trametinib is used in combination with dabrafenib, then both treatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dose modifications are necessary for only one of the two treatments are detailed below for pyrexia, uveitis, RAS mutation positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).
Dose modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions
Pyrexia
) for dose modifications for dabrafenib. No dose modification of trametinib is required when taken in combination with dabrafenib.Uveitis
No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld until resolution of ocular inflammation and then dabrafenib should be restarted reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib.
RAS-mutation-positive non-cutaneous malignancies
Consider the benefits and risks before continuing treatment with dabrafenib in patients with a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is required when taken in combination with dabrafenib.
Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction
Trametinib should be interrupted in patients who have an asymptomatic, absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the institution's lower limit of normal (LLN). No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If the LVEF recovers, treatment with trametinib may be restarted, but the dose should be reduced by one dose level with careful monitoring.
Trametinib should be permanently discontinued in patients with Grade 3 or 4 left ventricular cardiac dysfunction or clinically significant LVEF reduction which does not recover within 4 weeks.
Retinal vein occlusion (RVO) and Retinal pigment epithelial detachment (RPED)
If patients report new visual disturbances such as diminished central vision, blurred vision, or loss of vision at any time while on trametinib therapy, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with trametinib, whether given as monotherapy or in combination with dabrafenib, should be permanently discontinued. No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If RPED is diagnosed, follow the dose modification schedule in Table 3 below for trametinib.
Table 3 Recommended dose modifications for trametinib for RPED
|
Grade 1 RPED |
Continue treatment with retinal evaluation monthly until resolution. If RPED worsens follow instructions below and withhold trametinib for up to 3 weeks. |
|
Grade 2-3 RPED |
Withhold trametinib for up to 3 weeks. |
|
Grade 2-3 RPED that improves to Grade 0-1 within 3 weeks |
Resume trametinib at a lower dose (reduced by 0.5 mg) or discontinue trametinib in patients taking trametinib 1 mg daily. |
|
Grade 2-3 RPED that does not improve to at least Grade 1 within 3 weeks |
Permanently discontinue trametinib. |
Interstitial lung disease (ILD)/Pneumonitis
Withhold trametinib in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue trametinib for patients diagnosed with treatment-related ILD or pneumonitis. No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib for cases of ILD or pneumonitis.
Renal impairment
No dosage adjustment is required in patients with mild or moderate renal impairment. There are no data with trametinib in patients with severe renal impairment; therefore, the potential need for starting dose adjustment cannot be determined. Trametinib should be used with caution in patients with severe renal impairment when administered as monotherapy or in combination with dabrafenib.
Hepatic impairment
No dosage adjustment is required in patients with mild hepatic impairment. There are no clinical data in patients with moderate or severe hepatic impairment; therefore, the potential need for starting dose adjustment cannot be determined. Trametinib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with dabrafenib.
Non-Caucasian patients
The safety and efficacy of trametinib in non-Caucasian patients have not been established. No data are available.
Elderly
No initial dose adjustment is required in patients >65 years of age. More frequent dose adjustments (see Tables 1 and 2 above) may be required in patients >65 years of age.
Paediatric population
The safety and efficacy of trametinib has not been established in children and adolescents (<18 years). No data are available. Studies in juvenile animals have shown adverse effects of trametinib which had not been observed in adult animals.
Method of administration
Trametinib should be taken orally with a full glass of water. Trametinib tablets should not be chewed or crushed. Trametinib should be taken without food, at least 1 hour before or 2 hours after a meal.
It is recommended that the dose of trametinib is taken at a similar time every day. When trametinib and dabrafenib are taken in combination, the once-daily dose of trametinib should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.
If a patient vomits after taking trametinib, the patient should not retake the dose and should take the next scheduled dose.
Please refer to dabrafenib SmPC for information on method of administration when given in combination with trametinib.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
30 June 2014
Effect of other medicinal products on trametinib
As trametinib is metabolised predominantly via deacetylation mediated by hydrolytic enzymes (e.g. carboxyl-esterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions. Drug-drug interactions via these hydrolytic enzymes cannot be ruled out and could influence the exposure to trametinib.
Trametinib is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that strong inhibition of hepatic P-gp may result in increased levels of trametinib, caution is advised when co-administering trametininb with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole).
Effect of trametinib on other medicinal products
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics of other medicinal products via interaction with CYP enzymes or transporters. Trametinib may result in transient inhibition of BCRP substrates (e.g. pitavastatin) in the gut, which may be minimised with staggered dosing (2 hours apart) of these agents and trametinib.
Combination with dabrafenib
5 of the dabrafenib SmPC for interactions.Effect of food on trametinib
Patients should take trametinib as monotherapy or in combination with dabrafenib at least one hour prior to or two hours after a meal due to the effect of food on trametinib absorption.
