Search

BRAF-inhibitors have emerged as a promising targeted therapy for malignancies with BRAF mutations, particularly metastatic melanoma. However, granulomatous reactions including sarcoidosis and sarcoid-like-reactions have been reported as a consequence of BRAF-inhibition. It is important to adequately characterise these granulomatous reactions including cutaneous manifestations and systemic involvement, in order to guide investigations and management. A literature review was conducted to characterise the spectrum of granulomatous reactions associated with BRAF-inhibitors - identifying 55 reactions affecting 51 patients, with 37 reactions limited to cutaneous involvement. Further, possible correlation with cancer response, mechanisms of granuloma formation, as well as a proposed workup and management approach for these granulomatous reactions are presented.

New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

Background Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy. Objective We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib. Methods We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients. Results Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort. Limitations This study was limited by the small number of cases, all from a single institution. Conclusion Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.

BRAF inhibitors (BRAFi) cause paradoxical activation of the MAPK pathway in keratinocytes resulting in cutaneous squamous cell carcinoma (cuSCC).We sought to examine the clinical factors involved in BRAFi-induced cuSCC development.We studied 134 patients with BRAF-mutant metastatic melanoma treated with a BRAFi at Westmead Hospital, Sydney, Australia. Details of cuSCC development and associations with melanoma clinicopathologic features and treatment outcome were examined.In all, 32 (24%) patients developed 110 cuSCC after commencing treatment. In all, 61 (55%) cuSCC developed within the first 3 months. Age was the only independent risk factor for cuSCC development. After 3 months of therapy 4% of patients younger than 40 years developed cuSCC compared with 33% who were older than 60 years, and the hazard ratio of developing a cuSCC increased by 1.7 (95% confidence interval 1.3-2.3) per decade (P.001). BRAFi cuSCC occurred more often in sun-protected areas (42%) compared with sporadic cuSCC (21%) (P.001). cuSCC was not associated with progression-free survival.The study was from a single center and patients were also at risk of sporadic cuSCC.Most BRAFi-induced cuSCC develop within 3 months of BRAFi therapy. The only independent risk factor is increasing age. cuSCC may present in anatomical locations with low ultraviolet exposure such that thorough dermatologic assessment is required.

Background BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events. Objective We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens. Methods We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described. Results The development of cutaneous adverse events was significantly less frequent ( P = .012) and occurred after longer treatment time ( P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen ( P = .008). Patients receiving vemurafenib developed more cutaneous adverse events ( P = .001) and in particular more photosensitivity ( P = .010) than patients who did not. Limitations There were a limited number of patients. Conclusion Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy.