Encorafenib

Encorafenib is a potent and highly selective, ATP-competitive inhibitor of RAF kinases. Mutations such as BRAF V600E leave the BRAF kinase permanently active, which keeps the RAF/MEK/ERK (MAPK) pathway switched on and drives tumour-cell growth. Encorafenib shuts this signal down in cells with mutated BRAF but not in cells with wild-type BRAF, so it is used only when the tumour carries the mutation and always together with a second medicine.

Mechanism of Action

• BRAF and CRAF inhibition: in enzyme assays the half-maximal inhibitory concentration (IC50) was 0.35 nM for BRAF V600E, 0.47 nM for wild-type BRAF and 0.30 nM for CRAF. Encorafenib comes off its target slowly (dissociation half-life above 30 hours), which prolongs suppression of phosphorylated ERK.
• Mutation-selective effect: it suppresses RAF/MEK/ERK signalling in tumour cells expressing BRAF V600E, V600D and V600K, and it inhibits the growth of BRAF V600E, D and K mutant melanoma cells and of BRAF V600E colorectal cancer cells in vitro and in vivo. It does not inhibit this signalling in cells with wild-type BRAF.
• With binimetinib (melanoma, lung cancer): binimetinib blocks MEK, the next kinase down the same pathway. Together the two medicines give higher anti-tumour activity than either alone, and in mouse xenograft studies the combination also delayed the emergence of resistance.
• With cetuximab (colorectal cancer): a main route of resistance to RAF inhibitors in BRAF-mutant colorectal cancer is re-activation of the epidermal growth factor receptor (EGFR), which bypasses BRAF. Combining encorafenib with the EGFR antibody cetuximab improved anti-tumour activity in non-clinical models, and adding 5-fluorouracil and oxaliplatin (FOLFOX) improved anti-tumour efficacy in clinical studies.
• Other kinases: in vitro, encorafenib also bound other kinases (JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4 and STK36) at clinically achievable concentrations.

Pharmacokinetics

• Absorption: rapid; median time to peak 1.5 to 2 hours, and at least 86% of an oral dose is absorbed. A high-fat, high-calorie meal lowered the peak concentration by 36% without changing total exposure (AUC), so the capsules can be taken with or without food. A gastric pH-altering medicine (rabeprazole) did not change exposure. Exposure is approximately dose-linear; steady state is reached within 15 days, with an accumulation ratio of about 0.5 that is probably due to auto-induction of CYP3A4. Variability between patients is wide (AUC coefficient of variation 12.3% to 68.9%).
• Distribution: 86.1% bound to human plasma proteins in vitro; blood-to-plasma ratio 0.58; apparent volume of distribution about 226 L.
• Metabolism: the main route of clearance (about 88% of the recovered radioactivity). The predominant reaction is N-dealkylation, with hydroxylation, carbamate hydrolysis, indirect glucuronidation and glucose-conjugate formation also involved. The enzymes are mainly CYP3A4, with smaller contributions from CYP2C19 and CYP2D6.
• Elimination: after a radiolabelled 100 mg dose, radioactivity was excreted equally in faeces and urine (mean 47.2% each); only 1.8% of the radioactivity in urine was unchanged encorafenib. Apparent clearance was 27.9 L/h and the median terminal half-life 6.32 hours (range 3.74 to 8.09 hours).
• Special populations: mild to severe hepatic impairment may raise exposure. No dose adjustment is needed for patients aged 65 and over or for mild to moderate renal impairment (population analysis); there are no clinical data in severe renal impairment. No interaction was evidenced between encorafenib and cetuximab or FOLFOX.

Encorafenib is always used in combination with another medicine. Before treatment, the BRAF mutation must be confirmed with a CE-marked in vitro diagnostic test or, if none is available, another validated test. Efficacy and safety have been established only for melanoma with a BRAF V600E or V600K mutation and for colorectal cancer and lung cancer with a BRAF V600E mutation; encorafenib must not be used for melanoma, colorectal cancer or lung cancer with wild-type BRAF.

• Melanoma: with binimetinib, for adults with unresectable or metastatic melanoma with a BRAF V600 mutation.
• Colorectal cancer, after prior therapy: with cetuximab, for adults with metastatic colorectal cancer with a BRAF V600E mutation who have received prior systemic therapy.
• Colorectal cancer, first line: with cetuximab and FOLFOX, for the first-line treatment of adults with metastatic colorectal cancer with a BRAF V600E mutation.
• Non-small cell lung cancer (NSCLC): with binimetinib, for adults with advanced NSCLC with a BRAF V600E mutation.

• Hypersensitivity to encorafenib or to any of the excipients.

The side effects depend on the combination. The most common (in more than 25% of patients) with encorafenib plus binimetinib were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy or other muscle disorders, and joint pain. With cetuximab they were fatigue, nausea, diarrhoea, acne-like skin inflammation (acneiform dermatitis), abdominal pain, joint or musculoskeletal pain, decreased appetite, rash and vomiting. With cetuximab and FOLFOX they were peripheral neuropathy, neutropenia, nausea, fatigue, anaemia, diarrhoea, vomiting, decreased appetite, rash, thrombocytopenia, abdominal pain, haemorrhage, joint or musculoskeletal pain, pyrexia, constipation, mucosal inflammation and infection. Treatment was stopped because of an adverse reaction in 1.9% of patients taking encorafenib with cetuximab and in 3.5% of those taking it with cetuximab and FOLFOX.

The SmPC gives frequencies separately for each combination. Below, each reaction is listed under the highest frequency category reported for the three authorised combinations (with binimetinib; with cetuximab; with cetuximab and FOLFOX).

Very common (≥1/10): blood and lymphatic system: anaemia, neutropenia, thrombocytopenia, leukopenia; immune system: hypersensitivity; metabolism and nutrition: decreased appetite, hypokalaemia, hypomagnesaemia, hypoalbuminaemia; psychiatric: insomnia; nervous system: peripheral neuropathy, headache, dizziness, dysgeusia; eye: visual impairment, retinal pigment epithelial detachment; vascular: haemorrhage, hypertension; gastrointestinal: nausea, vomiting, diarrhoea, constipation, abdominal pain, mucosal inflammation; skin: rash, dry skin, pruritus, hyperkeratosis, alopecia, acneiform dermatitis, skin hyperpigmentation, palmar-plantar erythrodysaesthesia syndrome (hand-foot skin reaction); musculoskeletal: arthralgia or musculoskeletal pain, myopathy or muscle disorders, pain in extremity, back pain; general: fatigue, pyrexia, peripheral oedema; infections: infections; investigations: raised gamma-glutamyltransferase, raised transaminases, raised blood creatine phosphokinase, raised lipase, weight loss; neoplasms: melanocytic naevus. Some of these were very common with one combination only: neutropenia, thrombocytopenia, leukopenia, hypersensitivity, infections, weight loss, raised lipase, hypokalaemia, hypomagnesaemia and hypoalbuminaemia with cetuximab and FOLFOX; visual impairment, retinal pigment epithelial detachment, hypertension, peripheral oedema, dizziness and raised creatine phosphokinase with binimetinib.

Common (≥1/100 to <1/10): neoplasms: cutaneous squamous cell carcinoma (including keratoacanthoma), skin papilloma, new primary melanoma, basal cell carcinoma; infections: upper respiratory tract infection, sepsis; cardiac: left ventricular dysfunction, supraventricular tachycardia; eye: uveitis; vascular: venous thromboembolism; gastrointestinal: colitis; skin: erythema, panniculitis, photosensitivity, skin exfoliation; renal: renal failure (including acute kidney injury); investigations: raised blood creatinine, raised alkaline phosphatase, raised amylase.

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

Not known: tumour lysis syndrome (reported with binimetinib).

Important serious reactions: cutaneous squamous cell carcinoma (including keratoacanthoma) occurred in 3.0% of patients taking encorafenib with binimetinib and in 1.4% and 1.2% of those taking it with cetuximab and with cetuximab plus FOLFOX; new primary melanoma occurred in 1.9% and 0.8% of the two cetuximab groups. Haemorrhage occurred in 16.7% of patients with binimetinib, 21.3% with cetuximab and 32.8% with cetuximab plus FOLFOX; cerebral or intracranial haemorrhage affected 6 of 372 patients on the binimetinib combination and was fatal in 4. With binimetinib, uveitis occurred in 3.5% of patients, retinal pigment epithelial detachment in 22.3% (mostly Grade 1 or 2) and visual impairment in 23.1%; uveitis and visual impairment were generally reversible. Left ventricular dysfunction, venous thromboembolism, pancreatitis, rhabdomyolysis, renal failure and tumour lysis syndrome (which may be fatal) have also been reported. Patients aged 75 or older taking the binimetinib combination had more Grade 3 or higher reactions (62.9% versus 47.5%) and more reactions leading to treatment discontinuation (25.7% versus 7.4%) than patients under 75.

Encorafenib is cleared mainly by CYP3A4 and appears to induce this enzyme itself (its exposure at steady state is lower than after the first dose), so interactions can run in both directions.

• Strong CYP3A4 inhibitors (ritonavir, itraconazole, clarithromycin, telithromycin, posaconazole, grapefruit juice): posaconazole raised encorafenib exposure (AUC) about 3-fold in healthy volunteers, and model-based predictions suggest roughly 5-fold for ketoconazole. Avoid the combination; if it cannot be avoided, monitor the patient carefully for safety.
• Moderate CYP3A4 inhibitors (amiodarone, erythromycin, fluconazole, diltiazem, amprenavir, imatinib): diltiazem doubled exposure. Use with caution and monitor safety.
• CYP3A4 inducers: a strong inducer was not tested in a clinical study, but lower encorafenib exposure and reduced efficacy are likely. St John’s wort induces CYP3A and should be used only with caution.
• Hormonal contraceptives: encorafenib may reduce their effect. Women using them should add or switch to a barrier method (for example a condom) during treatment and for at least 1 month after the last dose.
• Anticoagulants and antiplatelet medicines: may increase the risk of haemorrhage.
• Medicines that prolong the QT interval: encorafenib itself may cause small increases in QTc, so QT risk factors should be controlled and electrolytes corrected (see Special Instructions).
• Gastric acid-reducing medicines: rabeprazole did not alter encorafenib exposure.
• Cetuximab and FOLFOX: no drug interaction with encorafenib was evidenced.
• Grapefruit: avoid grapefruit and grapefruit juice.
• Partner medicines: see the SmPC of binimetinib, cetuximab and the FOLFOX components for their own interactions. Further interactions of encorafenib are described in section 4.5 of the SmPC.

Treatment must be started and supervised by a physician experienced in the use of anticancer medicinal products, after the BRAF mutation has been confirmed. The capsules are swallowed whole with water, with or without food. Grapefruit juice should be avoided. Patients who cannot swallow the capsules may open them and disperse the contents in about 20 mL of apple sauce, to be taken immediately.

Recommended Dose

• Melanoma and lung cancer (with binimetinib): 450 mg (six 75 mg capsules) once daily. Binimetinib is dosed according to its own SmPC.
• Colorectal cancer (with cetuximab, or with cetuximab and FOLFOX): 300 mg (four 75 mg capsules) once daily. The doses and dose changes of cetuximab and of the FOLFOX components follow their own product information.

Dose Adjustments

• Side effects may require a dose reduction, a temporary interruption or permanent discontinuation. With binimetinib (melanoma, lung cancer) the dose levels are 450 mg once daily at the start, 300 mg (four 75 mg capsules) after the first reduction and 225 mg (three 75 mg capsules) after the second.
• Melanoma: there are limited data for a further reduction to 100 mg once daily. Stop permanently if 100 mg (two 50 mg capsules) once daily is not tolerated.
• Lung cancer: stop permanently if 225 mg (three 75 mg capsules) once daily is not tolerated.
• Specific reactions, for example Grade 3 or higher haemorrhage, uveitis, QT prolongation, liver laboratory abnormalities and creatinine elevation, are managed by interruption, dose reduction or discontinuation according to the tables in section 4.2 of the SmPC. For the colorectal cancer indication, see the SmPC for the dose-modification steps.

Special Populations

• Elderly: no dose adjustment for patients aged 65 and over.
• Hepatic impairment: in mild impairment (Child-Pugh A) use encorafenib with caution at 300 mg once daily. No dosing recommendation can be made for moderate (Child-Pugh B) or severe (Child-Pugh C) impairment, and without clinical data it is not recommended.
• Renal impairment: no adjustment for mild or moderate impairment. There are no clinical data in severe impairment, so the need for adjustment cannot be determined and the medicine should be used with caution.
• Children and adolescents: safety and efficacy have not been established; no data are available.

Combination Treatment and Mutation Testing

Encorafenib is never used alone. The warnings and precautions of binimetinib, cetuximab, 5-fluorouracil, folinic acid and oxaliplatin (see their SmPCs) apply to the respective combinations. Data are limited for the combination with binimetinib in melanoma patients who have already progressed on a BRAF inhibitor, and they suggest that efficacy is lower. Efficacy data are also limited in patients whose melanoma or lung cancer has spread to the brain.

Left Ventricular Dysfunction

With binimetinib, a fall in left ventricular ejection fraction (LVEF), with or without symptoms, has been reported. LVEF should be assessed by echocardiogram or MUGA scan before starting, one month later and then about every 3 months, or more often if needed. The combination has not been established in patients whose baseline LVEF is below 50% or below the lower limit of normal, so binimetinib should be used with caution in them. For symptomatic left ventricular dysfunction, a Grade 3 or 4 fall in LVEF or an absolute fall of 10% or more from baseline, both binimetinib and encorafenib should be stopped and LVEF checked every 2 weeks until recovery.

Haemorrhage

Haemorrhages, including major bleeding, can occur. The risk may be higher with anticoagulant and antiplatelet treatment. Grade 3 or higher haemorrhage is managed with dose interruption or discontinuation.

Eye Problems

Uveitis, iritis and iridocyclitis can occur with encorafenib, and retinal pigment epithelial detachment with the binimetinib combination. Patients should be asked at every visit about new or worsening visual disturbance. Diminished central vision, blurred vision or loss of vision calls for a prompt ophthalmological examination.

QT Prolongation

QT prolongation has been seen with BRAF inhibitors. No thorough QT study has been done with encorafenib, but results suggest mild increases in heart rate and small increases in the QTc interval, and a clinically significant exposure-dependent effect cannot be excluded. Electrolyte abnormalities (including magnesium and potassium) should be corrected and risk factors such as congestive heart failure and bradyarrhythmias controlled before and during treatment. An ECG is recommended before starting, one month later and then about every 3 months, or more often if needed. QTc prolongation is managed by dose reduction, interruption or discontinuation.

New Primary Malignancies

• Skin cancers: cutaneous squamous cell carcinoma (including keratoacanthoma) and new primary melanoma have been seen with BRAF inhibitors. A dermatological examination is advised before starting, every 2 months during treatment and for up to 6 months after it ends. Suspicious lesions should be excised and examined, and patients should report new skin lesions at once. Encorafenib is continued without dose change.
• Non-skin cancers: because of its mechanism, encorafenib may promote cancers associated with RAS activation. A head and neck examination, chest and abdominal CT, anal and pelvic examinations (for women) and complete blood counts are advised before, during and at the end of treatment as appropriate. Permanent discontinuation should be considered in patients who develop a RAS mutation-positive non-skin cancer, and benefits and risks should be weighed carefully in patients with a past or current RAS-associated cancer.

Tumour Lysis Syndrome

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

Liver and Kidney Function

• Liver tests: raised AST and ALT have been seen. Liver laboratory values should be checked before treatment and at least monthly for the first 6 months, then as clinically indicated, and abnormalities managed by interruption, dose reduction or discontinuation.
• Hepatic impairment: as encorafenib is cleared mainly by the liver, exposure may rise in mild to severe impairment. It is not recommended in moderate or severe impairment because there are no clinical data. In mild impairment closer monitoring is advised, including clinical examination, liver function tests and ECG as appropriate.
• Kidney function: raised creatinine is common. Renal failure, including acute kidney injury, has generally been linked to vomiting and dehydration, with diabetes and hypertension as other contributors. Creatinine should be monitored as clinically indicated and patients should drink enough fluid. Use with caution in severe renal impairment, where no data exist.

Pregnancy, Breastfeeding and Fertility

• Contraception: women who can become pregnant must use effective contraception during treatment and for at least 1 month after the last dose. Because encorafenib may reduce the effect of hormonal contraceptives, an additional or alternative barrier method is advised.
• Pregnancy: no data in pregnant women; animal studies showed reproductive toxicity. Encorafenib is not recommended during pregnancy or in women of childbearing potential who are not using contraception. A patient who becomes pregnant on treatment must be told of the potential hazard to the foetus.
• Breastfeeding: it is unknown whether encorafenib or its metabolites pass into breast milk, and a risk to the infant cannot be excluded. A decision must be made whether to stop breastfeeding or to stop treatment.
• Fertility: no human data. Animal findings suggest that fertility in men may be affected, and male patients should be told of the possible risk of impaired sperm production.

Effect on Driving

Encorafenib has a minor influence on the ability to drive and use machines. Visual disturbances have been reported. Patients should not drive or use machines if they have visual disturbances or other reactions that affect their ability.

Braftovi capsules need no cold chain. Store them below 30 °C in the original package to protect them from moisture. They are supplied in perforated unit-dose blisters (50 mg: packs of 28 or 112 capsules; 75 mg: packs of 42 or 168 capsules; not all pack sizes may be marketed). Keep out of the sight and reach of children.

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

Prescription only (Rx), on the prescription of a specialist experienced in cancer treatment, once a validated test has confirmed the BRAF mutation. Encorafenib capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription.