We searched PubMed with the terms “vemurafenib”, “PLX4032”, “dabrafenib”, “GSK2118436”, “BRAF inhibitors”, “sorafenib”, and “BAY43-9006”. We also sourced relevant articles referenced by other papers and abstracts from clinical meetings held within the last 5 years. All papers reviewed were available in full text and published in English. The last search date was June 25, 2012.
ReviewCutaneous toxicities of RAF inhibitors
Introduction
BRAF is mutated in roughly 50% of melanomas,1, 2, 3, 4, 5 and in papillary thyroid cancer and other malignancies in lesser frequencies, and results in the constitutive activation of the mitogen-activated protein (MAP) kinase pathway. Although 70–95% of BRAF mutations in melanoma are of the Val600Glu genotype, 5–30% are mutations of other genotypes, including Val600Lys, which occurs in up to 27% of patients with BRAF-mutant melanoma, particularly in geographical locations of high ultraviolet exposure.1, 2, 6, 7
RAF inhibitors can be divided into two types depending on their mode of action. Type 1 RAF inhibitors bind and inhibit the active conformation of the kinase, whereas type 2 RAF inhibitors bind to the inactive conformation of the kinase.8, 9
The potent new-generation type 1 RAF inhibitors8, 9 vemurafenib and dabrafenib (table 1), are the emerging standard of care for Val600Glu BRAF-mutant metastatic melanoma10, 11, 12, 13, 14, 15 with Response Evaluation Criteria In Solid Tumors (RECIST) response rates of about 50%. More than 90% of patients have a clinical benefit, and both overall survival and progression-free survival are longer than with dacarbazine.12, 15 The drugs are well tolerated, but cutaneous toxicities are common because of paradoxical activation of the MAP kinase pathway in wild-type BRAF cells.23, 24 LGX81825 is another type 1 RAF inhibitor under investigation in phase 1 clinical trials in metastatic melanoma (table 1).17
The type 2 RAF inhibitor sorafenib (table 1) was designed before the identification of BRAF mutations in cancer, and binds to RAF1, and wild-type BRAF and mutant BRAF, with little selectivity for one isoform over the other. It also inhibits other kinases including VEGFR2 (also known as KDR), VEGFR3 (also known as FLT4), PDGF, p38 MAPK, FLT3, KIT, and RET.26, 27 In clinical trials, sorafenib did not improve clinical outcomes for patients with metastatic melanoma when added to chemotherapy,28, 29 even in patients with BRAF-mutation-positive disease.21, 27, 30 Sorafenib is used in unresectable hepatocellular carcinoma and metastatic renal-cell carcinoma.31 Similarly, the type 2 RAF inhibitor RAF265 (table 1), which inhibits RAF1, Val600Glu mutant BRAF, wild-type BRAF, PDGFRB, KIT, and VEGFR2, showed little specific activity in mutant-metastatic melanoma in a phase 1 study,20 but unlike sorafenib, skin toxicities have not been reported.
BMS908662 (previously XL281) is a RAF inhibitor of unknown type; however, cutaneous toxicities caused by paradoxical activation of the MAP kinase pathway occur at rates similar to those of type 1 RAF inhibitors (table 1).18, 32 Other RAF inhibitors of unknown type that have been investigated in preclinical models include GDC0879,16 AZ628,19 PF04880594,17 and ARQ736 (table 1). ARQ736 is under investigation in a clinical trial (NCT01225536), but data regarding cutaneous toxicities are not available.
This Review summarises the cutaneous toxicities associated with type 1 and 2 RAF inhibitors, with particular focus on sorafenib and the new generation RAF inhibitors vemurafenib and dabrafenib.
Section snippets
Cutaneous side-effects of sorafenib
The most frequently reported adverse events associated with sorafenib are diarrhoea, nausea, fatigue, and hypertension;31, 33, 34, 35 however, cutaneous toxicities occur in up to 93% of patients.31, 34, 35 The most common cutaneous toxicities reported are an erythematous eruption in 35% of patients,36 hand-foot skin reaction (also known as palmar-plantar erythrodysesthesia syndrome) in up to 77% of patients,21, 31, 34, 35, 37, 38 androgenic-like alopecia (in 27%), curly hair, subungual
Cutaneous side-effects of vemurafenib and dabrafenib
A spectrum of cutaneous toxicities has been reported with both vemurafenib and dabrafenib. These include both benign and malignant lesions such as cutaneous squamous-cell carcinoma, verrucal keratosis, plantar hyperkeratotsis, Grover's disease, hair follicle changes, panniculitis, and photosensitivity.
Mechanisms of keratinocyte activation
Two similar hypotheses of paradoxical activation of the MAP kinase pathway by RAF inhibitors in wild-type BRAF cells might explain how RAF inhibitors induce or trigger growth of hyperkeratotic lesions.23, 24 Both hypotheses postulate that heterodimerisation and homodimerisation of RAF isotypes lead to activation of MEK (also known as MAP2K) via RAF1 (figure 4), although they differ in the precise mechanism by which the RAF inhibitor assists dimer formation. Heidorn and colleagues23 postulate
Combination BRAF and MEK inhibitors
The combination of the new generation type 1 RAF inhibitor dabrafenib and the MEK inhibitor trametinib has resulted in a significant reduction in cutaneous toxicities compared with the incidence reported with BRAF inhibitors alone.66, 67, 68 Similarly, in the phase 1 study of RO512676669 (a single agent with combined RAF and MEK inhibitor activity), no cutaneous squamous-cell carcinomas were reported in 53 patients, although other skin toxicities were common. In preclinical models, the RAF
Management of cutaneous toxicity
No guidelines for the management of cutaneous toxicities associated with new generation type 1 RAF inhibitors have been published, and the recommendations below are based on common practice and our own experience.
The management of these toxicities depends on their grade and the extent of distress caused to the patient (table 2). The overall goal is to treat the skin toxicities and prevent disruption in administration of the RAF inhibitor. Patients should undergo a dermatological review at
Conclusion
The new generation type 1 RAF inhibitors vemurafenib and dabrafenib are associated with several cutaneous toxicities. Most of these are grade 1 or 2 in severity and can be managed without the need to cease or modify the dose of the RAF inhibitor. The induction of cutaneous squamous-cell carcinoma and a possible link to the formation of wild-type BRAF primary melanomas suggests that all patients taking a RAF inhibitor should undergo regular dermatological assessments to identify and remove such
Search strategy and selection criteria
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