Abstract
PurposeVemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.Patients and MethodsPatients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.ResultsVemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).ConclusionVemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.
Highlights
A variety of unspecific toxicities of cytotoxic agents which emerge in skin, mucosa and adnexa are common
Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/ 28 patients (93%) experienced cutaneous side effects
Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy)
Summary
A variety of unspecific toxicities of cytotoxic agents which emerge in skin, mucosa and adnexa are common. Multiple other cutaneous side effects are observed including keratoacanthomas, invasive squamous cell carcinomas and melanomas.[9,10,11,12]. Vemurafenib (formerly called PLX4032, RG7204, RO5185426) was the first selective BRAF inhibitor to be developed in a clinical setting. This potent inhibitor, orally available, has shown significant impact on both progression-free and overall survival throughout phase I-III clinical trials (BRIM-1, BRIM-2, BRIM-3). [9,13] There is some evidence that the use of a mutation specific BRAF inhibitor leads to a paradoxical activation of the MAPK pathway in cells wild type for BRAF, resulting in cutaneous neoplasias in case of mutations upstream such as RAS. Attention regarding the cutaneous side effects of this drug has been mainly devoted to keratinocytic neoplasias such as keratoacanthomas and squamous cell carcinomas, which were seen in 18 to 24% of patients. [9,13] There is some evidence that the use of a mutation specific BRAF inhibitor leads to a paradoxical activation of the MAPK pathway in cells wild type for BRAF, resulting in cutaneous neoplasias in case of mutations upstream such as RAS. [15] far more cutaneous side effects are being observed under treatment and have an important impact on drug tolerance as well as on quality of life
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