BRAF and MEK Pathway Inhibitors

BRAF inhibitors block the mutant BRAF V600 kinase, and MEK inhibitors block the downstream MEK kinase in the MAPK signalling cascade. Used together, they give higher response, longer duration and fewer skin toxicities than BRAF inhibitor alone. They are used in melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, and other tumours with BRAF V600E mutation.

Classification. BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) and MEK inhibitors (trametinib, cobimetinib, binimetinib).

Pharmacokinetics. Mainly CYP3A4 and CYP2C8 metabolism; dabrafenib and vemurafenib induce CYP3A4, which lowers hormonal contraceptive effect.

• Dabrafenib 150 mg twice daily (1 hour before or 2 hours after a meal) with trametinib 2 mg once daily.
• Vemurafenib 960 mg twice daily with cobimetinib 60 mg once daily on days 1 to 21 of a 28-day cycle.
• Encorafenib 450 mg once daily with binimetinib 45 mg twice daily; in colorectal cancer encorafenib 300 mg once daily with cetuximab.

Differences. Dabrafenib with trametinib causes pyrexia in over half of patients; vemurafenib with cobimetinib causes photosensitivity, rash and QT prolongation; encorafenib with binimetinib causes less pyrexia but more nausea and retinal effects.

• Testing: confirm BRAF V600E or V600K mutation in tumour tissue or plasma; BRAF inhibitors do not work in wild-type tumours and can accelerate growth.
• Melanoma: unresectable or metastatic disease and adjuvant treatment (dabrafenib with trametinib for 12 months) after resection of stage III disease.
• Other tumours: BRAF V600E non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer (encorafenib with cetuximab), and low-grade glioma in children.
• Pyrexia: a temperature of 38.0 degrees Celsius or more is an indication to hold both drugs, give an antipyretic and fluids, and restart when settled at the same or a reduced dose; for recurrent fever give prednisolone 10 mg daily.
• Monotherapy with a BRAF inhibitor: avoid, because paradoxical activation of MAPK signalling causes cutaneous squamous cell carcinoma and keratoacanthoma.

Selection. Always give a BRAF inhibitor with a MEK inhibitor. Rapid disease or high lactate dehydrogenase favours targeted therapy first; immunotherapy for slower disease.

Contraindications. Wild-type BRAF tumour; pregnancy; severe liver impairment; uncontrolled QT prolongation.

Adverse effects. Pyrexia, rash, fatigue, nausea, diarrhoea, hypertension, haemorrhage, cardiomyopathy (fall in left ventricular ejection fraction), serous retinal detachment and retinal vein occlusion (MEK inhibitors), uveitis, hepatotoxicity, venous thromboembolism, hyperglycaemia, and new skin cancers.

Interactions. Strong CYP3A4 inhibitors (ritonavir-boosted regimens, azoles, clarithromycin) and inducers (rifampicin, phenytoin) change exposure; dabrafenib and vemurafenib reduce hormonal contraceptive efficacy and affect warfarin; avoid QT-prolonging drugs with vemurafenib; proton pump inhibitors reduce absorption of some formulations.

Special groups.

• Pregnancy: contraindicated; use non-hormonal contraception.
• Breastfeeding: avoid.
• Children: dabrafenib with trametinib is used in BRAF V600E low-grade glioma at weight-based doses.
• Older adults: more adverse effects and dose interruptions.
• Kidney impairment: caution in severe.
• Liver impairment: avoid in moderate to severe.

Monitoring. Full skin examination before starting, every 2 months during treatment and for 6 months after stopping; ophthalmology review if visual symptoms; left ventricular ejection fraction at baseline, 1 month, and every 2 to 3 months; blood pressure, liver function, glucose, creatinine, and ECG with vemurafenib.

Referral and escalation. Visual disturbance, ejection fraction fall of 10 percentage points or more or below 50 percent, recurrent fever with hypotension or kidney injury, haemorrhage, and thromboembolism need urgent care.