BRAF inhibitors, such as vemurafenib, dabrafenib, and encorafenib, are effective targeted therapies for BRAF V600 mutant malignancies such as melanoma. Dabrafenib is also approved for use in anaplastic thyroid cancer, non-small cell lung cancer, and pediatric low-grade gliomas. Encorafenib is approved to treat non-small cell lung cancer and colorectal cancer. Vemurafenib is additionally indicated for BRAF V600 positive Erdheim-Chester disease. BRAF inhibitors are frequently combined with MEK inhibitors, as this combination has been shown to improve response rate and overall survival in patients with BRAF V600E melanoma.

BRAF inhibitor therapy is associated with a wide spectrum of adverse events, including cutaneous toxicities. Cutaneous toxicities are more common in patients receiving BRAF inhibitors alone compared to those receiving combination therapy with BRAF plus MEK inhibitors.

A maculopapular (exanthematous) eruption is among the most common reported cutaneous toxicity, in up to 45% of patients. Onset is typically within the first 3 weeks of treatment. Female sex is a risk factor for the development of more severe rash.

This eruption is graded along the following scale:

• Grade 1: rash involving < 10% body surface area (BSA)
• Grade 2: rash involving 10%-30% BSA
• Grade 3: rash involving > 30% BSA or symptoms limit self-care activities of daily life
• Grade 4: life-threatening rash, requires urgent intervention

Photosensitivity reactions have been reported in up to 30% of patients on vemurafenib but are significantly less common with dabrafenib or encorafenib. Photosensitivity may occur within minutes of sunlight exposure. In addition, BRAF inhibitors are associated with radiosensitization leading to exacerbation of radiation dermatitis during or within 7 days following radiation therapy.

Cutaneous squamous cell carcinomas and keratoacanthomas are seen in up to 36% of patients, developing within 2-6 months after therapy initiation, with the majority occurring in the first 3 months. These are rarely observed in patients younger than age 40. Risk factors include a prior history of cutaneous squamous cell carcinoma, a diagnosis of melanoma, and treatment with vemurafenib. Seborrheic keratoses, verrucous keratoses, a keratosis pilaris-like eruption, milia, and epidermal cysts are also seen from BRAF inhibitor treatment.

Changes to existing melanocytic lesions and eruptive nevi, characterized by the sudden development of 10 or more benign-appearing melanocytic lesions within weeks to months, are reported. Eruptive nevi may appear anywhere on the body but have a predilection for sun-protected sites. The eruptive nevi usually persist, but they may regress after discontinuation of treatment.

Hand-foot skin reaction (HFSR) can affect up to 60% of patients receiving vemurafenib and is less frequent with other agents. BRAF inhibitor-induced panniculitis is rarely reported but is a specific cutaneous effect. Cases resemble erythema nodosum. It is less frequent among patients who receive combination BRAF and MEK therapy compared to those on monotherapy. Sweet syndrome (acute febrile neutrophilic dermatosis) is another rare reaction that has been reported with BRAF inhibitors.

Severe cutaneous adverse reactions include Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS), also known as DRESS (drug eruption with eosinophils and systemic symptoms). These reactions are rare and are reported to occur within 2 weeks of therapy initiation. Patients treated with vemurafenib are at higher risk. An increased risk of DIHS in patients with prior immune checkpoint inhibitor treatment has been reported.

Hair changes include telogen effluvium (8%-36% of patients) and changes to hair structure (ie, straight to curly, seen in 27% of patients).

Other more rarely reported eruptions and lesions include an acneiform eruption, transient acantholytic dermatosis (Grover disease), vitiligo, and granulomatous reactions, including sarcoidosis and sarcoid-like reactions.