Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma

Carlos, Giuliana; Anforth, Rachael; Clements, Arthur; Menzies, Alexander M.; Carlino, Matteo S.; Chou, Shaun; Fernández‐Peñas, Pablo

doi:10.1001/jamadermatol.2015.1745

Cited by 140 publications

(112 citation statements)

References 32 publications

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“…The trial identified most commonly grade 2 or 3 side effects including arthralgias, rash, nausea, photosensitivity, fatigue, cutaneous squamous cell carcinoma, pruritus, and palmar-plantar dysesthesia. Interestingly, photosensitivity is more common with vemurafenib (38.9%) in comparison to other BRAF inhibitors such as dabrafenib (0.8%) 38 . A total of 8 patients in the dose-escalation phase and 10 patients in the extension cohort experienced the development of cutaneous squamous cell carcinoma (SCC).…”

Section: Braf Inhibitor – Preclinicalmentioning

confidence: 99%

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Kim

Cohen

2016

Expert Opinion on Drug Discovery

118

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Introduction In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAFV600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAFV600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAFV600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen. Areas Covered Here we examine vemurafenib's journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials. Expert Opinion Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAFV600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6-8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.

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Section: Braf Inhibitor – Preclinicalmentioning

confidence: 99%

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Kim

Cohen

2016

Expert Opinion on Drug Discovery

118

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“…Agents that target and inhibit the MAPK (RAS–RAF–MEK–ERK–MAP) pathway and the mTOR pathway are demonstrating unique efficacy in children with central nervous system (CNS) tumors . Therapeutic inhibition of these pathways is associated with a high incidence of cutaneous reactions in adults . The most common cutaneous adverse events to BRAF inhibitors include follicular eruptions, verrucous papillomas, hand–foot skin reaction, photosensitivity, and alopecia .…”

Section: Introductionmentioning

confidence: 99%

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross‐sectional study

Song

Zhong

Kieran

et al. 2019

Pediatric Blood & Cancer

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Background MAPK (RAS–RAF–MEK–ERK–MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors. Methods In this cross‐sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one‐year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow‐up skin examinations were recommended every three months. Results Twenty‐two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3–19). Median time from treatment initiation to skin examination was 4.5 months (range, 0–43). Ninety‐six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions. Conclusions Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life‐saving therapy.

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“…The most frequently seen squamoproliferative disorders under BRAF inhibition therapy are verrucal keratosis, Grover disease, plantar hyperkeratosis, actinic keratosis, cutaneous squamous cell carcinoma, and keratosis pilaris 1, 2, 3, 4. More rare types of BRAF inhibitor–induced proliferation affecting eccrine glands described as eccrine syringometaplasia have also been reported 5 …”

Section: Discussionmentioning

confidence: 99%

Multiple palpebral syringomas occurring after initiation of BRAF inhibition therapy in a patient with metastatic melanoma

et al. 2016

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Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma

Cited by 140 publications

References 32 publications

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross‐sectional study

Multiple palpebral syringomas occurring after initiation of BRAF inhibition therapy in a patient with metastatic melanoma

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