BRAF-MEK INHIBITOR COMBINATION DECREASE DERMATOLOGICAL ADVERSE EVENTS

Eruptive melanocytic nevi are observed in patients receiving the multikinase inhibitor sorafenib (Nexavar) and the selective BRAF inhibitor vemurafenib (Zelboraf). In a case reported in JAMA Dermatology, Shen et al found that the addition of the MEK inhibitor cobimetinib to vemurafenib in a woman who developed eruptive melanocytic nevi during vemurafenib treatment for metastatic melanoma resulted in involution of eruptive melanocytic nevi.

Development of Eruptive Melanocytic Nevi During Response to Vemurafenib

A woman in her 20s with metastatic melanoma began treatment with vemurafenib as part of a clinical trial after disease progression on high-dose bolus interleukin 2. Dermatologic adverse effects of vemurafenib included hair thinning and alopecia of the scalp, eyebrows, and eyelashes, diffuse xerosis (including thick scalp scale), marked photosensitivity, and biopsy-confirmed erythema nodosum. She was observed to develop numerous small, eruptive, banal-appearing nevi, particularly on the trunk, which stabilized in number by 6 months of vemurafenib therapy. Baseline nevi both darkened and lightened during treatment, with no clinical or dermoscopic features suggesting malignant transformation. Vemurafenib produced compete response lasting for 18 months.

Combined BRAF and MEK Inhibition

Imaging in May 2012 showed that the patient had pulmonary metastases and metastatic lymphadenopathy in the head and neck, mediastinum, and portacaval region. She began treatment with vemurafenib 960 mg twice daily plus cobimetinib 60 mg/day on a 21 days on/7 days off schedule as part of a clinical trial. The patient exhibited gradual complete response, with imaging through June 2014 indicating no evidence of recurrence or metastatic disease. Adverse events of combination treatment included pyrexia, facial flushing, headache, and gastrointestinal tract symptoms, with all being more severe during early treatment. The periodic erythema nodosum persisted, but other vemurafenib-related cutaneous symptoms decreased, including reduction in scalp scale and diffuse xerosis, full regrowth of scalp, eyebrow, and eyelash hair, and, markedly reduced photosensitivity.

Involution of Eruptive Melanocytic Nevi

At 4 months after starting combination therapy, the eruptive melanocytic nevi, along with many preexisting nevi, had faded in color and clinical involution of most of the tan to brown nevi that developed during vemurafenib monotherapy was observed; some degree of clinical and dermoscopic involution was observed in nearly all nevi. At 16 months after the start of combination therapy, most of the eruptive nevi had faded on clinical and dermoscopic evaluation. The patient declined biopsy to confirm whether histopathologic complete nevus involution had occurred. However, clinical and dermoscopic evaluation every 3 months, photographic comparison, and updated total body mole mapping showed no features of severe dysplasia or early melanoma in any of the baseline or eruptive nevi, and no clinical halo phenomenon or dermoscopic regression structures were observed.

The investigators concluded: “Our case report describing the involution of [eruptive melanocytic nevi] supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon.”

Susan M. Swetter, MD, of Stanford University Medical Center, is the corresponding author for theJAMA Dermatology article.

The authors reported no conflicts of interest.