Background: Both D and T have demonstrated clinical activity as monotherapies and in combination in BRAF mutation–positive melanoma. However, the mechanism of acquired drug resistance and toxicity are not fully understood. We plan to investigate the sequential effects of BRAF and MEK inhibition on skin, blood, and tumor biomarkers, as well as to study correlations between biomarkers and response to treatment and toxicity. Methods: This is a 3-arm, open-label, randomized, phase 2 biomarker study in France, comparing the upfront combination of D with T versus their combination after 8 weeks of monotherapy treatment with D or T. As of the end of January 2014, 1 patient was randomized. Approximately 54 eligible patients, ≥ 18 years of age, with histologically confirmed stage IIIc or IV cutaneous melanoma and BRAF V600E/K mutation-positive disease will be randomized 1:1:1 to one of three treatment arms. In the monotherapy arms, treatment will be given for 8 weeks continuously (D 150 mg BID or T 2 mg QD) before other drug is dosed. In the combination arm, both drugs, at the respective doses above, will be given upfront. All treatments will be given until disease progression, death, or unacceptable toxicity. The primary objective of this trial is to evaluate biomarkers linked to treatment response, resistance, and toxicity when D and T are given as monotherapy and/or in combination. The secondary objectives are to evaluate the clinical response (overall response rate), as well as the exposures of the 3 arms in connection to clinical response and toxicity, and to characterize the safety profile of D and T in monotherapy and/or in combination. In addition, exploratory objectives are to evaluate changes in inflammation, the impact of the 2 drugs, separately and in combination, on the immune system, progression-free survival, and duration of response. The primary endpoint will be analyzed with a descriptive intent only. Hence, no hypothesis testing will be performed. Clinical trial information: EudraCT number 2012-004577-12.