Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516