Introduction The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival... Show moreIntroduction The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile. Results Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity. Conclusion Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective. Show less
Melanoma is a malignancy that arises from melanocytes, the pigment-producing cells that can be predominantly found in the eye or the epidermal basal layer of the skin. Mainly due to increased UV... Show moreMelanoma is a malignancy that arises from melanocytes, the pigment-producing cells that can be predominantly found in the eye or the epidermal basal layer of the skin. Mainly due to increased UV exposure, the incidence of melanoma has doubled worldwide over the past three decades (200.000 new cases in 2008). Primary melanomas can be easily treated by surgical resection, leading to a good prognosis for stage I patients. However, metastasized melanoma is almost completely resistant to therapeutic modalities such as radio- and chemotherapy, resulting in a median overall survival of less than one year for this patient group. Despite considerable efforts, for over 20 years there was no melanoma treatment developed that could improve survival of stage IV patients. However, the treatment of unresectable metastasized melanoma has progressed markedly in recent years due to the development of both immunotherapies that stimulate anti-tumor immunity and targeted therapies that block oncogenic proteins. This thesis will focus on pre-clinical work concerning the optimization of melanoma treatment. In detail, it will address for both targeted therapies and immunotherapies factors that play a role in the identification of response-predictive biomarkers, the toxicity of treatments, and the potential efficacy of combination treatments. Show less
