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Original Investigation |

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

Giuliana Carlos, MBBS1,2; Rachael Anforth, BMed1,2; Arthur Clements, BSc (Med), MBBS2,3,4,5; Alexander M. Menzies, MBBS2,3,4,5; Matteo S. Carlino, MBBS2,3,4,5; Shaun Chou, MBBS6; Pablo Fernandez-Peñas, MD, PhD1,2
[+] Author Affiliations
1Department of Dermatology, Westmead Hospital, Sydney, Australia
2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia
3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia
4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, Australia
5Melanoma Institute Australia, Sydney, Australia
6Department of Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Westmead, Australia
JAMA Dermatol. 2015;151(10):1103-1109. doi:10.1001/jamadermatol.2015.1745.
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Importance  The cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before.

Objective  To compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients.

Design, Setting, and Participants  We performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013.

Main Outcomes and Measures  Multiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment.

Results  The most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs 31 [26.1%]; P < .001), verrucal keratosis (0 vs 79 [66.4%]; P < .001), and Grover disease (0 vs 51 [42.9%]; P < .001).

Conclusions and Relevance  This study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.

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Representative Cutaneous Adverse Effects of Study Drugs

A, Multiple verrucal keratosis. Widespread presence of hyperkeratotic papules on both lower extremities in a patient treated with vemurafenib. B, Grover disease. The trunk of a patient with extensive itchy erythematous papules appearing after vemurafenib treatment. C, Photosensitivity. Moderate facial erythema localized to the nose, malar areas, and lips after minimal sun exposure in a patient treated with vemurafenib. No blisters were present. D, Acneiform reaction. Multiple comedones and pustules on the back of a patient treated with combined dabrafenib mesylate and trametinib dimethyl sulfoxide. No cysts were present.

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