Binimetinib

Binimetinib is a reversible, ATP-uncompetitive inhibitor of the kinase activity of MEK1 and MEK2 (mitogen-activated extracellular signal-regulated kinases 1 and 2). MEK proteins are upstream regulators of the ERK pathway, which promotes cell proliferation. In melanoma and other cancers this pathway is often switched on by mutated forms of BRAF, which activates MEK. Binimetinib is always given together with encorafenib, a BRAF inhibitor.

Mechanism of Action

• MEK inhibition: binimetinib prevents the activation of MEK by BRAF and inhibits MEK kinase activity. In cell-free systems it inhibits MEK1 and MEK2 at concentrations (IC50) of 12–46 nM.
• Anti-tumour activity: 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 encorafenib: the two medicines block two different kinases in the same MAPK pathway (BRAF and MEK), which gives higher anti-tumour activity than either alone. In mouse models of BRAF V600E melanoma the combination also delayed the emergence of resistance.
• Mutation dependence: the efficacy and safety of the combination have been established only in melanoma with BRAF V600E or V600K mutations and in non-small cell lung cancer with a BRAF V600E mutation. It must not be used in BRAF wild-type disease.

Pharmacokinetics

• Absorption: rapid, with a median time to peak concentration of about 1.5 hours; at least 50% of a dose is absorbed. With twice-daily dosing together with encorafenib, steady state is reached within 15 days with no major accumulation (mean steady-state Cmax 654 ng/mL and AUC 2.35 µg·h/mL in melanoma patients, from population modelling). Exposure is approximately dose-linear. A high-fat, high-calorie meal lowered the peak concentration by 17% without changing the AUC, and a gastric pH-altering agent (rabeprazole) did not change exposure.
• Distribution: about 97.2% bound to human plasma proteins in vitro; blood-to-plasma ratio 0.718; apparent volume of distribution about 374 L.
• Metabolism: mainly by glucuronidation, which accounts for up to about 61% of its clearance (UGT1A1). Other routes are N-dealkylation, amide hydrolysis and loss of an ethane-diol group from the side chain. About 60% of the circulating radioactivity in plasma was binimetinib itself. In vitro, CYP1A2 and CYP2C19 form an active metabolite that represents less than 20% of binimetinib exposure in patients.
• Elimination: after a single radiolabelled 45 mg dose in healthy subjects, a mean of 62.3% of the radioactivity was eliminated in faeces and 31.4% in urine. The mean terminal half-life is about 3.5 hours, and the apparent clearance about 20.2 L/h.
• Special populations: no dose adjustment is recommended in patients aged 65 or over, in mild hepatic impairment (Child-Pugh A) or in renal impairment. Binimetinib is not recommended in moderate or severe hepatic impairment (see Administration and Dosage).

Binimetinib is used in adults, always in combination with encorafenib.

• Melanoma: unresectable or metastatic melanoma with a BRAF V600 mutation.
• Non-small cell lung cancer (NSCLC): advanced NSCLC with a BRAF V600E mutation.

The BRAF mutation must be confirmed before treatment (see Administration and Dosage).

• Hypersensitivity to binimetinib or to any of the excipients.

The safety of binimetinib 45 mg twice daily with encorafenib 450 mg once daily was assessed in 372 patients: 274 with BRAF V600 mutant unresectable or metastatic melanoma and 98 with BRAF V600E mutant advanced NSCLC. The most common reactions (in more than 25% of patients) were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy and muscle disorders, and arthralgia. With encorafenib 300 mg once daily plus binimetinib (257 melanoma patients), the most common reactions were fatigue, nausea and diarrhoea.

Very common (≥1/10): anaemia; peripheral neuropathy, dizziness, headache; visual impairment, retinal pigment epithelial detachment; haemorrhage (bleeding at various sites, including cerebral, gastrointestinal and urinary tract bleeding), hypertension; abdominal pain, diarrhoea, vomiting, nausea, constipation; hyperkeratosis, rash, dry skin, pruritus, alopecia; arthralgia, myopathy and muscle disorders (including myalgia, muscular weakness and muscle spasm), back pain, pain in extremity; pyrexia, peripheral oedema, fatigue; increased blood creatine phosphokinase, increased transaminases, increased gamma-glutamyltransferase.

Common (≥1/100 to <1/10): cutaneous squamous cell carcinoma (including keratoacanthoma), skin papilloma; hypersensitivity (including angioedema and urticaria); dysgeusia; uveitis; left ventricular dysfunction (including decreased ejection fraction and heart failure); venous thromboembolism (including pulmonary embolism and deep vein thrombosis); colitis; photosensitivity, acneiform dermatitis, palmar-plantar erythrodysaesthesia syndrome, erythema, panniculitis; renal failure; increased blood creatinine, alkaline phosphatase, amylase and lipase.

Uncommon (≥1/1,000 to <1/100): basal cell carcinoma, facial paresis, pancreatitis, rhabdomyolysis.

Not known: tumour lysis syndrome.

With encorafenib 300 mg once daily, some reactions fell into a lower frequency category than with the 450 mg combination: anaemia, peripheral neuropathy, haemorrhage, hypertension and pruritus (common instead of very common), and colitis, increased amylase and increased lipase (uncommon instead of common).

Reactions that need active monitoring are left ventricular dysfunction, haemorrhage, eye disorders (retinal pigment epithelial detachment, retinal vein occlusion, uveitis), raised creatine phosphokinase and rhabdomyolysis, hypertension, venous thromboembolism, pneumonitis or interstitial lung disease, new skin and other cancers, tumour lysis syndrome and liver test abnormalities.

Binimetinib is cleared mainly by glucuronidation through UGT1A1, so its interaction profile is limited, but some combinations call for caution. For the interactions of encorafenib, which is always given with it, see the encorafenib SmPC.

• UGT1A1 inducers and inhibitors: effects are unlikely to be clinically relevant but have not been tested in a formal clinical study. Inducers (such as rifampicin and phenobarbital) and inhibitors (such as indinavir, atazanavir and sorafenib) should be co-administered with caution. Encorafenib is a relatively potent reversible UGT1A1 inhibitor, yet no difference in binimetinib exposure was seen when the two were given together.
• CYP1A2 and P-glycoprotein inducers: inducers of CYP1A2 (such as carbamazepine and rifampicin) and of P-glycoprotein transport (such as St John’s wort or phenytoin) may lower binimetinib exposure and so its efficacy.
• CYP1A2 substrates: binimetinib is a potential inducer of CYP1A2; take care with sensitive substrates such as duloxetine or theophylline.
• OAT3 substrates: binimetinib is a weak inhibitor of OAT3; take care with sensitive substrates such as pravastatin or ciprofloxacin.
• Anticoagulants and antiplatelet medicines: the risk of bleeding may be increased.
• Acid-reducing medicines: a gastric pH-altering agent (rabeprazole) did not change binimetinib exposure.
• Food: the tablets can be taken with or without food.

Binimetinib treatment in combination with encorafenib must be started and supervised by a physician experienced in the use of anticancer medicinal products. Before treatment, the BRAF V600E mutation must be confirmed with a CE-marked in vitro diagnostic medical device for that purpose, or with another validated test if no CE-marked device is available. The combination is not to be used in patients with wild-type BRAF melanoma or wild-type BRAF NSCLC. The tablets are swallowed whole with water, with or without food. For patients who cannot swallow, the 15 mg tablets may be dispersed in a small glass (about 10 mL) of water, orange juice or apple juice and taken immediately; the glass is then rinsed with about 10 mL of the same liquid, which is also drunk immediately.

Recommended Dose

• 45 mg twice daily, about 12 hours apart (three 15 mg tablets or one 45 mg tablet each time; total daily dose 90 mg), together with encorafenib, dosed according to its own SmPC.
• Treatment continues until the patient no longer benefits or unacceptable toxicity occurs.

Dose Adjustments for Side Effects

• Reduced dose: 30 mg twice daily. A reduction below 30 mg twice daily is not recommended; if 30 mg twice daily is not tolerated, treatment is stopped.
• Re-escalation: a return to 45 mg twice daily may be considered if the reaction that caused the reduction is under effective management. It is not recommended if the reduction was for left ventricular dysfunction or for any Grade 4 toxicity.
• With encorafenib: when a toxicity occurs with the combination, both medicines are reduced, interrupted or stopped together. Exceptions where only encorafenib is adjusted are palmar-plantar erythrodysaesthesia syndrome, uveitis (including iritis and iridocyclitis) and QTc prolongation. If binimetinib is interrupted temporarily, encorafenib is reduced to 300 mg once daily for that time; if binimetinib is stopped permanently, encorafenib is stopped. If encorafenib is interrupted, binimetinib is interrupted too, and if encorafenib is stopped permanently, binimetinib is stopped.

The SmPC tables set out the following actions for selected reactions (graded by NCI CTCAE).

• Rash: Grade 2: maintain the dose; if the rash worsens or does not improve within 2 weeks, withhold until Grade 0 or 1 and resume at the same dose (first occurrence) or a reduced dose (recurrent Grade 2). Grade 3: withhold until Grade 0 or 1, then resume at the same dose (first occurrence) or a reduced dose (recurrent). Grade 4: permanently discontinue.
• Retinal pigment epithelial detachment (symptomatic, Grade 2 or 3): withhold for up to 2 weeks and repeat the eye monitoring, including visual acuity. If improved to Grade 0 or 1, resume at the same dose; if improved to Grade 2, resume at a lower dose; if not improved to Grade 2, permanently discontinue. Grade 4 with reduced visual acuity, or retinal vein occlusion: permanently discontinue.
• Decreased left ventricular ejection fraction (LVEF): for Grade 2, or an asymptomatic absolute fall of more than 10% from baseline that is below the lower limit of normal, evaluate LVEF every 2 weeks and withhold for up to 4 weeks; resume at a reduced dose if LVEF is back at or above the lower limit of normal and the fall from baseline is 10% or less, otherwise permanently discontinue. Grade 3 or 4 decrease, or symptomatic left ventricular dysfunction: permanently discontinue and evaluate LVEF every 2 weeks until recovery.
• Creatine phosphokinase (CK) rise or rhabdomyolysis: Grade 3 without symptoms (CK above 5 to 10 times the upper limit): keep the dose and ensure good hydration. Grade 4 without symptoms (above 10 times): withhold until Grade 0 or 1, with hydration. Grade 3 or 4 with muscle symptoms or renal impairment: withhold until Grade 0 or 1; if resolved within 4 weeks resume at a reduced dose, otherwise permanently discontinue.
• Venous thromboembolism: uncomplicated deep vein thrombosis or pulmonary embolism up to Grade 3: withhold; resume at a reduced dose if improved to Grade 0 or 1, otherwise permanently discontinue. Grade 4 pulmonary embolism: permanently discontinue.
• Liver test abnormalities: Grade 2 (AST or ALT above 3 to 5 times the upper limit): keep the dose; if no improvement within 2 weeks, withhold until Grade 0 or 1 or baseline, then resume at the same dose. First Grade 3 (AST or ALT above 5 times the upper limit with bilirubin above 2 times) or first Grade 4 (AST or ALT above 20 times): withhold for up to 4 weeks and resume at a reduced dose if improved, otherwise permanently discontinue (for Grade 4, permanent discontinuation is also an option). Recurrent Grade 3: consider permanent discontinuation. Recurrent Grade 4: permanently discontinue.
• Interstitial lung disease or pneumonitis: Grade 2: withhold for up to 4 weeks and resume at a reduced dose if improved to Grade 0 or 1, otherwise permanently discontinue. Grade 3 or 4: permanently discontinue.
• Other reactions: recurrent or intolerable Grade 2, or a first Grade 3: withhold for up to 4 weeks and resume at a reduced dose if improved to Grade 0 or 1 or baseline, otherwise permanently discontinue. First Grade 4: the same, or permanent discontinuation straight away. Recurrent Grade 3: consider permanent discontinuation. Recurrent Grade 4: permanently discontinue.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years and older.
• Hepatic impairment: no dose adjustment in mild impairment (Child-Pugh A). Encorafenib is not recommended in moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, so binimetinib is not recommended in these patients either.
• Renal impairment: no dose adjustment is recommended.
• Children and adolescents: safety and efficacy have not been established; no data are available.

Missed or Vomited Dose

• A missed dose should not be taken if it is less than 6 hours until the next dose is due.
• If vomiting occurs after a dose, the dose is not repeated; the next scheduled dose is taken as usual.

Use With Encorafenib

Binimetinib is only given together with encorafenib; the warnings for encorafenib are in its own SmPC. Data are limited for patients who have progressed on a BRAF inhibitor, in whom the combination is expected to be less effective, and efficacy data are limited in patients with brain metastases.

Left Ventricular Dysfunction

Symptomatic or asymptomatic decreases in ejection fraction can occur. LVEF should be assessed by echocardiogram or MUGA scan before starting binimetinib, 1 month after starting, and then about every 3 months or more often as clinically indicated. Safety has not been established in patients whose baseline LVEF is below 50% or below the institutional lower limit of normal, so binimetinib is used with caution in them. For any symptomatic left ventricular dysfunction, Grade 3 or 4 LVEF decrease, or an absolute fall of 10% or more from baseline, it should be discontinued and LVEF evaluated every 2 weeks until recovery.

Eye Disorders

Retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) can occur, and uveitis (including iridocyclitis and iritis) has been reported with the combination. Binimetinib is not recommended in patients with a history of RVO. Its safety has not been established in patients with risk factors for RVO, such as uncontrolled glaucoma, raised eye pressure, uncontrolled diabetes or a history of hyperviscosity or hypercoagulability syndromes, so it is used with caution in them. Patients are asked at each visit about new or worsening visual disturbance. New or worsening symptoms, including reduced central vision, blurred vision or loss of vision, call for a prompt eye examination. Symptomatic RPED is managed by interruption, dose reduction or discontinuation, and binimetinib is permanently discontinued for RVO. For uveitis, see the encorafenib SmPC.

Bleeding

Haemorrhages, including major bleeding events, can occur. The risk may be higher with anticoagulant and antiplatelet therapy. Grade 3 or higher bleeding is managed by interruption, dose reduction or discontinuation, as clinically indicated.

CK Elevation and Rhabdomyolysis

Symptom-free rises in creatine phosphokinase are seen, and rhabdomyolysis has been reported uncommonly. CK and creatinine should be monitored monthly during the first 6 months and as clinically indicated, and patients should keep up an adequate fluid intake. Particular care is needed in patients with neuromuscular conditions associated with CK elevation and rhabdomyolysis.

Hypertension

Hypertension, or worsening of existing hypertension, can occur. Blood pressure is measured at the start and monitored during treatment, and hypertension is controlled with standard therapy. In severe hypertension, binimetinib is interrupted temporarily until blood pressure is controlled.

Venous Thromboembolism

Venous thromboembolism, including pulmonary embolism, can occur. Binimetinib is used with caution in patients at risk of, or with a history of, venous thromboembolism. Events are managed by interruption, dose reduction or discontinuation.

Pneumonitis and Interstitial Lung Disease

Binimetinib is withheld in patients with suspected pneumonitis or interstitial lung disease, for example with new or progressive cough, breathlessness, hypoxia, reticular opacities or lung infiltrates. It is permanently discontinued if treatment-related pneumonitis or interstitial lung disease is diagnosed.

New Primary Cancers

New primary cancers, of the skin and elsewhere, have been seen with BRAF inhibitors and can occur when binimetinib is given with encorafenib.

• Skin cancers: cutaneous squamous cell carcinoma, including keratoacanthoma, has been seen. A skin examination by a dermatologist is done before starting, every 2 months during treatment and for up to 6 months after stopping. Suspicious lesions are removed and examined, patients should report any new skin lesion at once, and binimetinib and encorafenib are continued without dose change.
• Other cancers: from its mechanism, encorafenib may promote cancers associated with RAS activation. Before starting, during treatment and at the end, as clinically appropriate, patients have a head and neck examination, a chest and abdomen CT scan, anal and pelvic examinations (for women) and complete blood counts. Permanent discontinuation of both medicines should be considered if a RAS mutation-positive cancer develops, and the benefits and risks are weighed carefully in patients with a prior or concurrent RAS-associated cancer.

Tumour Lysis Syndrome

Tumour lysis syndrome, which can be fatal, has been associated with binimetinib given with encorafenib. Risk factors are a high tumour burden, chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. These patients are monitored closely and treated promptly, and preventive hydration should be considered.

Liver Test Abnormalities and Hepatic Impairment

Raised AST and ALT can occur. Liver tests are checked before starting and at least monthly during the first 6 months, then as clinically indicated, and abnormalities are managed by interruption, dose reduction or discontinuation. Binimetinib is cleared mainly in the liver by glucuronidation, and it is not recommended in moderate or severe hepatic impairment.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for at least 1 month after the last dose.
• Pregnancy: there are no data from pregnant women, and animal studies have shown reproductive toxicity. Binimetinib is not recommended in pregnancy or in women of childbearing potential who are not using contraception. A patient who is treated during pregnancy, or who becomes pregnant while taking it, should be told of the potential hazard to the foetus.
• Breastfeeding: it is not known whether binimetinib or its metabolite passes into human milk, and a risk to the breastfed infant cannot be excluded. A decision is made whether to stop breastfeeding or to stop Mektovi, weighing the benefit of breastfeeding for the child against the benefit of treatment for the mother.
• Fertility: there are no human data on the effect on fertility.

Lactose

Mektovi tablets contain lactose (133.5 mg in each 15 mg tablet and 234.9 mg in each 45 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

Binimetinib has a minor influence on the ability to drive or use machines. Visual disturbances have been reported, and patients should not drive or use machines if they have visual disturbances or any other reaction that may affect their ability to do so.

Mektovi tablets do not require any special storage conditions. They are supplied in PVC/PVDC/aluminium blisters: the 15 mg tablets in packs of 84 or 168 tablets (12 per blister) and the 45 mg tablets in packs of 28 or 56 tablets (14 per blister). Not all pack sizes may be marketed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a physician experienced in the use of anticancer medicinal products, who must start and supervise treatment. Binimetinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription. It is used only together with encorafenib, so the two medicines are prescribed and taken as one treatment, and a BRAF V600 mutation must have been confirmed with a validated test before treatment starts.