Trametinib

Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2. These kinases pass growth signals from RAS and RAF on to ERK, which controls cell proliferation, differentiation, survival and growth. In many melanomas and other cancers this pathway is permanently switched on by a BRAF V600 mutation (BRAF is mutated in about half of melanomas, and V600E and V600K make up most of these mutations), so blocking MEK slows the growth of the tumour cells.

Mechanism of Action

• MEK inhibition: trametinib binds MEK1 and MEK2 with high affinity and blocks both their activation by BRAF and their kinase activity. Because it binds the unphosphorylated enzyme, it also keeps MEK in its unphosphorylated, inactive form.
• BRAF V600 mutant tumours: it inhibits the growth of BRAF V600 mutant melanoma cell lines and has anti-tumour effects in animal models of BRAF V600 mutant melanoma.
• Combination with dabrafenib: dabrafenib inhibits RAF kinases, so the two medicines block two kinases of the same pathway at once. In laboratory studies the combination inhibited BRAF V600 mutation-positive tumour cells more strongly than either medicine alone and delayed the emergence of resistance in BRAF V600 mutation-positive melanoma xenografts.
• Mutation status: a BRAF V600 mutation must be confirmed by a validated test before treatment. Efficacy and safety have not been evaluated in melanoma that tested negative for the mutation.

Pharmacokinetics

• Absorption: median time to peak concentration is 1.5 hours. The mean absolute bioavailability of a 2 mg tablet is 72% compared with an intravenous microdose, and exposure rises in proportion to the dose on repeated dosing. At 2 mg once daily the steady-state geometric mean peak concentration is 22.2 ng/mL, the AUC 370 ng·h/mL and the pre-dose concentration 12.1 ng/mL (peak-to-trough ratio 1.8), with low variability between patients (below 28%). Trametinib accumulates on daily dosing (mean accumulation ratio 6.0) and reaches steady state by Day 15. A high-fat, high-calorie meal lowers the peak concentration by 70% and the AUC by 10%, which is why the tablets are taken without food.
• Distribution: 97.4% bound to human plasma proteins; volume of distribution about 1,200 L, determined after an intravenous microdose.
• Metabolism: mainly deacetylation, alone or together with mono-oxygenation, by carboxylesterases 1b, 1c and 2 (other hydrolytic enzymes may contribute); the deacetylated metabolite is then glucuronidated. Oxidation by CYP3A4 is a minor pathway. After single and repeated doses, unchanged trametinib is the main circulating component in plasma.
• Elimination: mean terminal half-life about 127 hours (5.3 days) after a single dose; intravenous plasma clearance 3.21 L/h. Because of the long half-life, less than 50% of a radiolabelled oral dose was recovered over 10 days. Drug-related material was excreted mainly in the faeces (over 80% of recovered radioactivity) and to a minor extent in urine (up to 19%); less than 0.1% of the excreted dose was unchanged trametinib in urine.
• Special populations: mild or moderate renal impairment does not change the dose. A clinical pharmacology study showed only a limited effect of moderate to severe hepatic impairment on exposure. Population analysis found no significant pharmacokinetic differences between Asian and Caucasian patients.

A BRAF V600 mutation must be confirmed in the tumour before treatment (see Administration and Dosage).

Melanoma

• Unresectable or metastatic melanoma with a BRAF V600 mutation: adults and adolescents aged 12 years and older, with trametinib alone or in combination with dabrafenib. Trametinib alone has not shown clinical activity in patients whose disease has progressed on a prior BRAF inhibitor.
• Adjuvant treatment of Stage III melanoma with a BRAF V600 mutation, following complete resection: adults and adolescents aged 12 years and older, in combination with dabrafenib.

Non-small cell lung cancer (NSCLC)

• Adults with advanced NSCLC with a BRAF V600 mutation, in combination with dabrafenib.

Differentiated thyroid cancer (DTC)

• Adults with locally advanced or metastatic DTC with a BRAF V600E mutation that is refractory to or not eligible for radioactive iodine (RAI) and has progressed during or after prior systemic therapy, in combination with dabrafenib.

Paediatric glioma (Spexotras oral solution)

• Low-grade glioma (LGG): paediatric patients aged 1 year and older with LGG with a BRAF V600E mutation who require systemic therapy, in combination with dabrafenib.
• High-grade glioma (HGG): paediatric patients aged 1 year and older with HGG with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment, in combination with dabrafenib.

• Hypersensitivity to trametinib or to any of the excipients (Mekinist tablets and Spexotras oral solution).

The most common side effects (at least 20% of patients) of trametinib alone are rash, diarrhoea, fatigue, peripheral oedema, nausea and acneiform dermatitis. With dabrafenib they are pyrexia, fatigue, nausea, rash, chills, diarrhoea, headache, arthralgia, vomiting, cough, haemorrhage and peripheral oedema. The frequencies below come from the SmPC tables: the combination with dabrafenib in 1,188 adults (melanoma, adjuvant melanoma, lung and thyroid cancer; mean treatment 16 months) and trametinib alone in 329 patients with melanoma.

Trametinib With Dabrafenib (Adults)

Very common (≥1/10): nasopharyngitis, urinary tract infection, neutropenia, anaemia, decreased appetite, headache, dizziness, hypertension, haemorrhage, cough, abdominal pain, constipation, diarrhoea, nausea, vomiting, dry skin, pruritus, rash, erythema, acneiform dermatitis, arthralgia, myalgia, pain in extremity, muscle spasms, fatigue, chills, asthenia, peripheral oedema, pyrexia, influenza-like illness, weight increased (reported in paediatric patients only), increased alanine and aspartate aminotransferase.

Common (≥1/100 to <1/10): cellulitis, folliculitis, paronychia, pustular rash, cutaneous squamous cell carcinoma, papilloma, seborrhoeic keratosis, thrombocytopenia, leukopenia, dehydration, hyponatraemia, hypophosphataemia, hyperglycaemia, peripheral neuropathy, blurred vision, visual impairment, uveitis, decreased ejection fraction, bradycardia, hypotension, lymphoedema, pneumonitis, dyspnoea, dry mouth, stomatitis, generalised exfoliative dermatitis, actinic keratosis, night sweats, hyperkeratosis, alopecia, palmar-plantar erythrodysaesthesia syndrome, skin lesion, hyperhidrosis, panniculitis, skin fissures, photosensitivity, renal failure and acute kidney injury, mucosal inflammation, face oedema, increased alkaline phosphatase, gamma-glutamyltransferase and creatine phosphokinase, potentiation of radiation toxicity.

Uncommon (≥1/1,000 to <1/100): new primary melanoma, acrochordon (skin tags), hypersensitivity, sarcoidosis, chorioretinopathy, retinal detachment, periorbital oedema, cardiac failure, left ventricular dysfunction, atrioventricular block, gastrointestinal perforation, pancreatitis, colitis, acute febrile neutrophilic dermatosis, rhabdomyolysis.

Rare (≥1/10,000 to <1/1,000): haemophagocytic lymphohistiocytosis, interstitial lung disease, nephritis.

Not known (cannot be estimated from the available data): tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), tattoo-associated skin reactions.

Trametinib Alone (Melanoma)

Very common (≥1/10): hypertension, haemorrhage, cough, dyspnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, rash, acneiform dermatitis, dry skin, pruritus, alopecia, fatigue, peripheral oedema, pyrexia, increased aspartate aminotransferase.

Common (≥1/100 to <1/10): folliculitis, paronychia, cellulitis, pustular rash, anaemia, hypersensitivity, dehydration, peripheral neuropathy, blurred vision, periorbital oedema, visual impairment, left ventricular dysfunction, decreased ejection fraction, bradycardia, lymphoedema, pneumonitis, stomatitis, erythema, palmar-plantar erythrodysaesthesia syndrome, skin fissures, cracked skin, face oedema, mucosal inflammation, asthenia, increased alanine aminotransferase, alkaline phosphatase and creatine phosphokinase.

Uncommon (≥1/1,000 to <1/100): chorioretinopathy, papilloedema, retinal detachment, retinal vein occlusion, cardiac failure, interstitial lung disease, gastrointestinal perforation, colitis, rhabdomyolysis.

Not known (cannot be estimated from the available data): atrioventricular block (including complete block).

Children (Spexotras With Dabrafenib)

In 171 paediatric patients in two studies, the most common side effects (at least 20%) were pyrexia (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), acneiform dermatitis (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and raised transaminases (22%). The most frequent severe (grade 3 or 4) reactions were neutropenia (15%), pyrexia (11%), raised transaminases (6%) and weight increase (5%). The profile was largely consistent with that in adults. Long-term data on growth and skeletal maturation are limited.

Important Serious Reactions

Haemorrhage, including major and fatal bleeding, can occur; fatal intracranial haemorrhage affected fewer than 1% of patients in the combination safety population. Left ventricular ejection fraction fell in about 8% of patients receiving the combination, mostly without symptoms and reversibly, usually 2 to 5 months after starting. Rash affects about 60% of patients on trametinib alone and about 27% on the combination, mostly grade 1 or 2. Liver enzyme rises are mostly grade 1 or 2, and over 90% of such events with trametinib alone occurred within the first 6 months. Fever is more frequent and more severe with the combination. Interstitial lung disease, visual disturbance (including retinal vein occlusion and retinal pigment epithelial detachment), hypertension and rhabdomyolysis have also been reported. See Special Instructions for what to do.

Trametinib is cleared mainly by hydrolytic enzymes rather than by CYP enzymes, so metabolic interactions with other medicines are unlikely, although interactions through these enzymes cannot be ruled out.

• Strong P-glycoprotein inhibitors (for example verapamil, ciclosporin, ritonavir, quinidine, itraconazole): trametinib is a P-gp substrate in vitro, and strong inhibition of hepatic P-gp could raise its levels, so caution is advised.
• BCRP substrates (for example pitavastatin): trametinib may briefly inhibit these in the gut; staggering the doses 2 hours apart reduces the effect. Trametinib is otherwise unlikely to change the levels of other medicines through CYP enzymes or transporters.
• Hormonal contraceptives: no loss of efficacy is expected with trametinib alone. With dabrafenib they may be less effective, so an additional barrier method is needed.
• Dabrafenib: when used together, the interactions in sections 4.4 and 4.5 of the dabrafenib SmPC also apply.
• Anticoagulants and antiplatelet medicines: may increase the risk of haemorrhage.
• Medicines with a recognised risk of gastrointestinal perforation: use with caution, particularly in patients with other risk factors.
• Radiation treatment: radiation toxicity can be potentiated when trametinib is given with dabrafenib before, during or after radiotherapy.
• Food: food lowers absorption. Take trametinib at least 1 hour before or 2 hours after a meal.

Treatment must be started and supervised by a physician experienced in anti-cancer medicinal products. Before treatment, the tumour’s BRAF V600 mutation (V600E for glioma) must be confirmed with a CE-marked in vitro diagnostic device; if none is available, an alternative validated test is used. The dose of dabrafenib given with trametinib is set out in the dabrafenib SmPC.

Tablets are taken by mouth with a full glass of water, not chewed or crushed, without food (at least 1 hour before or 2 hours after a meal) and at a similar time each day. With dabrafenib, the once-daily trametinib dose is taken at the same time every day, together with either the morning or the evening dose of dabrafenib.

Mekinist Tablets: Recommended Dose

• Adults: 2 mg once daily, regardless of body weight.
• Adolescents aged 12 to under 18 years with melanoma: by body weight: 26 to 37 kg, 1 mg once daily; 38 to 50 kg, 1.5 mg once daily; 51 kg or more, 2 mg once daily. A dose for tablets has not been established below 26 kg.
• Duration: until the patient no longer benefits or toxicity becomes unacceptable. In adjuvant melanoma, 12 months unless the disease recurs or toxicity is unacceptable.

Spexotras Oral Solution: Recommended Dose

Spexotras is given once daily in combination with dabrafenib dispersible tablets, in a volume of the reconstituted solution set by body weight (rounded to the nearest kg):

• 8 kg: 6 mL (0.30 mg)
• 9 to 10 kg: 7 mL (0.35 mg)
• 11 kg: 8 mL (0.40 mg)
• 12 to 13 kg: 9 mL (0.45 mg)
• 14 to 17 kg: 11 mL (0.55 mg)
• 18 to 21 kg: 14 mL (0.70 mg)
• 22 to 25 kg: 17 mL (0.85 mg)
• 26 to 29 kg: 18 mL (0.90 mg)
• 30 to 33 kg: 20 mL (1 mg)
• 34 to 37 kg: 23 mL (1.15 mg)
• 38 to 41 kg: 25 mL (1.25 mg)
• 42 to 45 kg: 28 mL (1.40 mg)
• 46 to 50 kg: 32 mL (1.60 mg)
• 51 kg or more: 40 mL (2 mg)

The dose for a body weight below 8 kg has not been established. Treatment continues until disease progression or unacceptable toxicity. Data in patients older than 18 years with glioma are limited, so continuing into adulthood depends on the individual balance of benefit and risk. The powder is reconstituted before use; follow the SmPC and the package leaflet.

Dose Adjustments for Side Effects

• Side effects may call for a dose reduction, an interruption or permanent discontinuation; the stepwise dose-level tables are in the SmPC and are not reproduced here.
• No dose change is recommended for cutaneous squamous cell carcinoma or a new primary melanoma (see the dabrafenib SmPC).
• With Spexotras, if treatment-related toxicity occurs, trametinib and dabrafenib are reduced, interrupted or stopped together.
• Specific triggers are described under Special Instructions: fever of 38 °C or above, suspected interstitial lung disease, retinal vein occlusion, retinal pigment epithelial detachment, falls in ejection fraction, severe skin reactions and life-threatening pulmonary embolism.

Special Populations

• Elderly: no initial dose adjustment above 65 years. Reactions leading to dose reduction, interruption or permanent discontinuation were more likely in patients aged 65 and over, so more frequent adjustments may be needed.
• Renal impairment: no adjustment in mild or moderate impairment; there are no data in severe impairment, so use with caution.
• Hepatic impairment: no adjustment in mild impairment; use with caution in moderate or severe impairment.
• Race: limited data in non-Caucasian patients; no dose adjustment is needed in Asian patients.
• Children and adolescents: Mekinist tablets have not been established below 18 years, except in adolescents aged 12 years and older with melanoma (see above). Spexotras is for children aged 1 year and older with glioma. Studies in juvenile animals showed adverse effects not seen in adult animals.

Missed or Vomited Dose

A missed trametinib dose is taken only if more than 12 hours remain until the next scheduled dose. With dabrafenib, a missed dabrafenib dose is taken only if more than 6 hours remain until the next one. If vomiting occurs after a dose, it is not repeated; the next dose is taken at the scheduled time.

BRAF V600 Mutation Testing

Treatment is only for tumours with a confirmed BRAF V600 mutation. Efficacy and safety have not been evaluated in melanoma that tested negative for it.

Use With Dabrafenib

When trametinib is combined with dabrafenib, the dabrafenib SmPC must be read before treatment starts, for its warnings and precautions as well.

Previous BRAF Inhibitor Treatment

Trametinib alone has not been compared with a BRAF inhibitor in a clinical study, and its response rates appear lower. After progression on a BRAF inhibitor, trametinib alone has shown no clinical activity, and the combination is likely to be less effective, so other options should be considered first. The best sequence of treatments after progression on a BRAF inhibitor has not been established.

New Malignancies

With dabrafenib, new cutaneous and non-cutaneous malignancies can occur. Cutaneous squamous cell carcinoma (including keratoacanthoma) and new primary melanoma can be managed by excision without changing treatment. Dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present; trametinib needs no dose change for RAS mutation-positive malignancies.

Haemorrhage

Major and fatal haemorrhages have occurred. The risk in patients with platelet counts below 75,000 is not known because they were excluded from studies. Antiplatelet or anticoagulant medicines may increase the risk. If bleeding occurs, treat as clinically indicated.

Heart Function and Blood Pressure

Trametinib can reduce the left ventricular ejection fraction (LVEF). LVEF should be assessed in all patients before treatment, one month after starting and then about every 3 months. Use caution in impaired left ventricular function; patients with left ventricular dysfunction, NYHA class II to IV heart failure, acute coronary syndrome in the past 6 months, clinically significant uncontrolled arrhythmias or uncontrolled hypertension were excluded from studies, so safety in them is unknown. Acute, severe left ventricular dysfunction due to myocarditis has been reported occasionally with the combination and recovered fully on stopping, so doctors should watch for new or worsening cardiac signs. Blood pressure should be measured at the start and monitored during treatment, and hypertension treated with standard therapy.

Pyrexia

Fever is more frequent and more severe with the combination and can come with severe rigors, dehydration and low blood pressure, sometimes leading to acute renal insufficiency. Interrupt trametinib (and dabrafenib, if given) when the temperature reaches 38 °C or above, and at the first symptom of fever if it recurs. Start an antipyretic such as ibuprofen or paracetamol, consider oral corticosteroids if these are not enough, and check for signs of infection. Restart when the fever has resolved; if it came with other severe signs, restart at a reduced dose.

Lung Disease

Interstitial lung disease or pneumonitis occurred in 2.4% of patients (5 of 211) in a phase III study of trametinib alone, all needing hospital care, and in about 1% or fewer in combination studies. Withhold trametinib in patients with suspected disease, such as new or worsening cough, dyspnoea, hypoxia, pleural effusion or infiltrates, and stop permanently if treatment-related interstitial lung disease or pneumonitis is diagnosed. Dabrafenib may continue at the same dose.

Eye Disorders

Retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) can occur, along with blurred vision, reduced acuity and other visual changes; uveitis and iridocyclitis have been reported with the combination. Trametinib is not recommended in patients with a history of RVO, and its safety is not established where RVO risk factors are present (uncontrolled glaucoma or raised eye pressure, uncontrolled hypertension or diabetes, hyperviscosity or hypercoagulability). Any new visual disturbance, such as reduced central vision, blurred vision or loss of vision, needs prompt ophthalmological assessment. Follow the SmPC dose-modification schedule for RPED and stop trametinib permanently for RVO.

Skin Reactions

Rash occurs in about 60% of patients on trametinib alone and about 27% on the combination, mostly grade 1 or 2 and rarely needing a dose change. Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and DRESS, which can be life-threatening or fatal, have been reported with the combination. Patients should be told the warning signs before treatment and watched closely; if they appear, dabrafenib and trametinib are withdrawn.

Liver, Muscle, Kidney and Pancreas

• Liver: liver function should be monitored every four weeks for 6 months after starting, then as clinically indicated. Moderate or severe hepatic impairment calls for caution, as trametinib is cleared by metabolism and biliary excretion.
• Muscle: rhabdomyolysis has been reported. Signs or symptoms need clinical evaluation and treatment as indicated; in severe cases, hospital care, interruption or permanent discontinuation was required.
• Kidney and pancreas: renal failure and pancreatitis have been reported with the combination (see the dabrafenib SmPC).

Thromboembolism

Deep vein thrombosis and pulmonary embolism can occur. Patients with breathlessness, chest pain, or arm or leg swelling should seek medical care immediately. Trametinib and dabrafenib are stopped permanently for life-threatening pulmonary embolism.

Gastrointestinal Disorders

Colitis and gastrointestinal perforation, including fatal cases, have been reported. Use caution in patients with risk factors: a history of diverticulitis, metastases to the gastrointestinal tract, or concomitant medicines with a recognised risk of perforation.

Other Serious Reactions With Dabrafenib

• Sarcoidosis: mostly affecting skin, lung, eye and lymph nodes. It should not be mistaken for disease progression, and treatment can usually continue.
• Haemophagocytic lymphohistiocytosis (HLH): if confirmed, both medicines are stopped and HLH is treated.
• Tumour lysis syndrome: may be fatal. Risk factors are high tumour burden, chronic renal insufficiency, oliguria, dehydration, low blood pressure and acidic urine. Monitor closely and consider prophylactic hydration.
• Radiation toxicity: radiation recall and sensitisation, mostly of the skin but sometimes of other sites such as the spinal cord, have been reported. Use caution with radiotherapy given at the same time or in sequence.

Pregnancy, Breastfeeding and Fertility

• Contraception: women who could become pregnant must use effective contraception during treatment and for 16 weeks after the last dose. With dabrafenib, hormonal contraceptives may be less effective, so a barrier method should be used instead.
• Pregnancy: trametinib should not be given to pregnant women. There are no adequate studies in pregnancy and animal studies showed reproductive toxicity. If it is used in pregnancy, or the patient becomes pregnant, she should be told of the possible hazard to the foetus.
• Breastfeeding: it is not known whether trametinib passes into human milk, and a risk to the infant cannot be excluded. It should not be given to breastfeeding mothers; a decision must be made to stop breastfeeding or trametinib.
• Fertility: there are no human data. Animal studies showed adverse effects on female reproductive organs, and trametinib may impair fertility in humans. Effects on spermatogenesis were seen in animals given dabrafenib.

Sodium

Each Mekinist tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Trametinib has a minor influence on the ability to drive and use machines. Patients should be aware that fatigue, dizziness or eye problems may affect these activities.

• Mekinist tablets: no special temperature requirement. Keep in the original package to protect from light and moisture, with the bottle tightly closed (the bottle has a child-resistant closure and contains a desiccant). Once the bottle is opened, store at not more than 30 °C and use within 30 days.
• Spexotras powder for oral solution: store in a refrigerator at 2–8 °C, in the original package to protect from light and moisture. Keep the cold chain unbroken during storage and transport. After reconstitution, store below 25 °C, do not freeze, and discard any unused solution 35 days after reconstitution.

• Mekinist tablets: 3 years in an unopened bottle; use within 30 days after opening.
• Spexotras powder for oral solution: 3 years; the reconstituted solution is discarded after 35 days.

Prescription only (Rx). Treatment is started and supervised by a physician experienced in anti-cancer medicinal products, after the tumour’s BRAF mutation has been confirmed. Mekinist tablets and Spexotras are taken at home, so they are supplied to the patient or to the treating clinic on prescription, with cold-chain delivery for the refrigerated Spexotras powder.