BRAF / MEK inhibitor cutaneous reactions
Dabrafenib + trametinib skin reactions; encorafenib + binimetinib skin reactions; BRAFi cutaneous toxicities; secondary cSCC from BRAF inhibition
BRAF inhibitor monotherapy (vemurafenib, dabrafenib, encorafenib) causes a characteristic constellation of cutaneous reactions including secondary keratoacanthomas and well-differentiated cSCCs from paradoxical RAS-MAPK pathway activation in wild-type keratinocytes, verrucous papillomas, hyperkeratosis, panniculitis and severe photosensitivity. Combining a BRAF inhibitor with a MEK inhibitor (trametinib, binimetinib) — now standard in BRAF V600+ melanoma — significantly reduces the secondary keratinocyte malignancy rate but introduces additional MEK-driven toxicities such as papulopustular folliculitis and central serous chorioretinopathy. Active skin surveillance during BRAF / MEK inhibitor therapy is mandatory.
Overview of toxicities
- BRAF inhibitor monotherapy — secondary KAs / cSCC, verrucous papillomas, hyperkeratosis, palmoplantar keratoderma, panniculitis, photosensitivity, alopecia, naevi changes.
- MEK inhibitor monotherapy — papulopustular folliculitis, paronychia, xerosis, photosensitivity, central serous chorioretinopathy.
- BRAF + MEK combination (e.g. dabrafenib + trametinib, encorafenib + binimetinib) — reduces BRAFi-specific keratinocyte toxicities to a fraction of monotherapy rates while introducing some MEKi-related effects; overall better-tolerated than either alone for skin.
Secondary keratoacanthomas and cSCC
- The most characteristic BRAFi-monotherapy toxicity — well-differentiated cSCCs or KAs typically arising in chronically sun-damaged skin within the first 8–26 weeks.
- Driven by paradoxical RAS-MAPK pathway activation in BRAF-wild-type keratinocytes harbouring RAS mutations (often HRAS).
- Rates with BRAFi monotherapy — 15–30%; with BRAF + MEK combination — < 5%.
- Management — surgical excision; complete excision is curative; do not interrupt BRAFi for individual lesions.
- Active skin surveillance every 4–8 weeks during BRAFi monotherapy; every 12 weeks on BRAF + MEK combination.
Photosensitivity and other BRAFi-specific
- UVA-mediated photosensitivity — severe burns and erythema on minimal UV exposure; counsel for strict SPF 50+ sun protection, hats, photoprotective clothing.
- Verrucous papillomas — multiple wart-like lesions on hands, face, trunk; cosmetic excision / cryotherapy.
- Palmoplantar keratoderma — painful thickening of palms / soles; emollients, urea creams, salicylic acid.
- Panniculitis with erythema-nodosum-like nodules — typically settles with NSAID or short steroid course; rarely needs drug interruption.
- Changes in pre-existing naevi — darkening, eruption of new naevi; routine surveillance.
MEK-inhibitor-specific effects
- Papulopustular folliculitis on face and chest — similar appearance to EGFRI papulopustular eruption. Managed with doxycycline + topical steroid.
- Paronychia — painful periungual inflammation; barrier creams, topical steroid, sometimes antimicrobial.
- Xerosis and pruritus — emollients.
- Photosensitivity (separate from BRAFi) — sunscreens.
- Central serous chorioretinopathy — uncommon ocular toxicity; needs ophthalmology referral if visual disturbance.
Practice points
- Baseline full skin examination before initiating BRAFi ± MEKi.
- Surveillance every 4–8 weeks on BRAFi monotherapy; every 12 weeks on combination.
- Educate patients — sun protection, low threshold for review of any new lesion.
- Develop a low threshold for biopsy / excision of new keratotic lesions; the secondary cSCCs are well-differentiated and rarely metastasise but should be excised.
- Most cutaneous toxicities respond to symptomatic management without requiring drug interruption.
References
- Su F et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med; 2012;366:207–15.
- Anforth R et al. Cutaneous adverse events of BRAF inhibitor therapy. Br J Dermatol; 2013.
- Long GV et al. Combined dabrafenib and trametinib in BRAF V600-mutant melanoma — COMBI-d and COMBI-v. N Engl J Med; 2014/2015.
Spot a correction?
If any clinical statement, citation or link on this page needs updating, please email admin@skinoncology.net with the page name, the proposed correction and the supporting source.