BRAF inhibitors are protein kinase inhibitors, selective for the activating mutation of the oncogenic BRAF serine-threonine kinase enzyme (BRAF V600 gene mutation) in metastatic melanoma.
There is a wide spectrum of skin toxicities with BRAF inhibitors, which include:rr
- secondary cutaneous malignancies
- squamous cell carcinoma (SCC)/keratoacanthoma
- basal cell carcinoma (BCC)
- new primary melanoma
- papilloma or verrucal keratosis
- plantar-palmar hyperkeratosis
- maculo-papular rash
- Grover's disease
- mild alopecia and other hair changes
- erythema nodosum-like panniculitis
- radiation recall reaction
- radiosensitisation.
MEK inhibitors, in particular trametinib, are associated with acneiform rash which can be observed when used in combination with BRAF inhibitors.
Combined BRAF/MEK inhibition
The prevalence of skin toxicities, including secondary cutaneous malignancies, is reduced with combined BRAF and MEK inhibition. This reduction is due to the addition of MEK inhibition of the MAP kinase pathway preventing the activation of upstream kinases paradoxically activated in wild-type BRAF keratinocytes. Patients may still experience some skin toxicities with combination treatment; however, they are less frequent and less severe e.g. keratoacanthomas and cutaneous squamous-cell carcinomas were observed at a lower frequency in the vemurafenib and cobimetinib combination group than in the single agent vemurafenib group (6% vs 24%). However, photosensitivity is more frequent in combination vemurafenib and cobimetinib compared to vemurafenib monotherapy or other BRAF/MEK inhibitor combinations. Stevens-Johnson syndrome and toxic epidermal necrolysis are serious adverse events that have been reported but are rare.
Management of skin toxicities is outlined below, although the frequency is low. Acneiform rash is usually transient if it occurs with the combination therapy, but often responds to clindamycin lotion (1%) and does not usually require dose modifications.
Skin toxicities associated with BRAF/MEK inhibitors
Skin toxicity |
Prevalence associated with drug (all grades) |
Vemurafenibrr |
Dabrafenibr |
Encorafenibr,r |
Vemurafenib-cobimetinibr |
Dabrafenib-trametinibr |
Encorafenib-binimetinibr,r |
Rash
Maculo-papular rash
Grover's disease
Acneiform rash |
36%
14%
NR
NR |
17%
NR
27%
NR |
21%
10%
NR
NR |
73%
15.4%
NR
NR |
23%
NR
NR
8% |
15%
2%
NR
NR |
Plantar-palmar hyperkeratosis* |
8% |
20% |
26% |
10% |
5% |
9% |
Photosensitivity |
33% |
NR |
4% |
48% |
NR |
5% |
Papilloma |
18% |
24% |
9% |
NR |
1% |
6% |
Cutaneous SCC/ keratoacanthoma |
24% (12% SCC) |
6% |
6% |
6% |
2% |
2% |
Basal cell carcinoma |
6% |
4% |
0.9% |
NR |
NR |
1.1% |
Adapted from Anforth et al 2013r
*Plantar-palmar hyperkeratosis and palmar-plantar erythrodysesthesia were both reported as “Hand-Foot Syndrome” in some of the studies; NR=not reported
Onset/duration
In a published review of reported time-to-lesion onset with BRAF monotherapy, data established general trends in lesion presentation, with inflammatory dermatoses peaking at 2 weeks post treatment initiation and SCC and SCC-related lesions peaking at 8-16 weeks.r Patients can continue to develop cutaneous adverse events after 52 weeks of continuous therapy.r In the vemurafenib and cobimetinib combination, rash had an early onset, with the majority occurring within the first three cycles of treatment. Photosensitivity displays no clear temporal pattern and occurs throughout the course of treatment.r
Secondary cutaneous malignancies
RAS mutations are frequent in patients who develop cutaneous squamous-cell carcinomas and keratoacanthomas and it is hypothesised that the paradoxical activation of mitogen activated protein kinase (MAPK) signalling accelerates the growth of these lesions.r The development of new primary melanomas is also attributed to this up-regulated pathway and occurs in approximately 1% of patients on BRAF inhibitors.
Squamous-cell carcinoma (SCC) and keratoacanthoma (KA)
- SCCs appear as tender, scaly or crusted lesions, which may subsequently form sores or ulcers that fail to heal. Size may vary from a few millimetres to several centimetres in diameter.
- KAs are flesh coloured to red nodules with a central keratotic area. BRAF induced KAs are often indistinguishable from SCCs.
- SCCs are found on both sun-exposed and sun-protected sites, particularly the face, lips, ears, hands, forearms and lower legs.
- Risk factors include age >65 years, prior skin cancer, clear eyes (blue/green) and chronic sun exposure.r
Papilloma or verrucal keratosis
- Benign wart like lesions with finger-like projections.
- Often occur in areas of increased friction such as skin-folds, but can occur anywhere.
- May be difficult to differentiate clinically between SCCs.
Maculo-papular rash (including Grover's disease)r
- Grover's disease is a benign acantholytic disorder that presents as scattered erythematous papules.
- Affects upper arms and trunk.
- Variable pruritus.
Plantar-palmar hyperkeratosisr
- Distinct from palmar-plantar erythrodysaesthesia or hand-foot skin reaction.
- Skin thickening at points of pressure or friction, mainly the soles of the feet and seldom the hands.
- Blisters are infrequent.
Alopecia and other hair changes
Several changes affecting the hair follicle have been associated with BRAF inhibitors. These changes include:
- alopecia (usually grade 1 but severe alopecia has been reported in some patients)
- changes in hair structure (e.g. straight to curly)
- changes in hair colour (turned grey)
- hair folliculitis
- keratosis pilaris.
Skin toxicities associated with BRAF inhibitorsrrr
(A) Verrucous papilloma
© Annals of Oncology 2013
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(B) Squamous cell carcinoma
© Archives of Dermatology 2012
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(C) Grover's disease
© Lancet Oncology 2013
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(D) Plantar hyperkeratosis
© Lancet Oncology 2013
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(E) Photosensitivity (vemurafenib)
© Annals of Oncology 2013
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