Molecular targeted therapy with BRAF inhibitor vemurafenib is now currently used as first
      line treatment for patients with unresectable stage IIIc or metastatic melanoma harboring the
      BRAFV600 mutation, which is present in about 50% of melanoma patients. Despite the
      improvement in Progression Free Survival (PFS) en Overall Survival (OS) compared to
      dacabarzine, acquired resistance that develops in virtually all patients treated with
      vemurafenib is a great concern.

      Combining a BRAF inhibitor with a MEK inhibitor that targets the MAPK pathway further
      downstream, however, may overcome acquired resistance to BRAF inhibition and recent studies
      in which both MEK inhibitors and BRAF inhibitors are combined as monotherapy seem promising.

      In a phase IB trial preliminary efficacy of vemurafenib with cobimetinib (GDC-0973), a highly
      selective inhibitor of MEK1 seems encouraging with an initial response rate of 85% and
      currently a phase III study of vemurafenib versus vemurafenib plus cobimetinib in BRAFV600
      mutation positive patients with advanced stage melanoma is underway. It is expected that in
      the near future combined BRAF and MEK inhibition will be standard of care for patients with
      BRAFV600 mutated metastatic melanoma.

      Diagnostic CT cannot assess reduction in tumor size within days after the initiation of
      therapy and anatomic size does not provide information about the development of therapy
      response or resistance at a molecular level. It has been clearly demonstrated that
      alterations in metabolism occur earlier than anatomical size reduction after the initiation
      of therapy. Molecular imaging with PET visualizes metabolic activity in tumors and is a
      sensitive method to detect alterations in cell metabolism, even shortly after the start of
      therapy. 18F-Fluorodeoxyglucose (18F-FDG) is used to visualize glucose metabolism, whereas
      18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT) is used to visualize proliferation. In
      preclinical mouse models 18F-FLT appears to predict response or resistance to therapy better
      than 18F-FDG. However, so far only 18F-FDG PET has been used to monitor response to
      vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of
      18F-FDG within 2 weeks following treatment. Preclinical studies and the observation that
      melanoma is a highly proliferative malignancy in most patients suggest that 18F-FLT might be
      the radiopharmaceutical of first choice in this setting.

      By detecting these metabolic alterations, responders might be distinguished from
      non-responders at an earlier phase compared with anatomical imaging with CT. This way,
      unnecessary expensive treatment of combined BRAF/MEK-inhibitor therapy and its side effects
      can be prevented in patients who will not benefit from this therapy. Furthermore, the level
      of decline in metabolic activity in the first two weeks after the initiation of therapy might
      predict progression free survival (PFS) as preliminary results in literature suggest.

      This is a single arm explorative phase II clinical trial in 90 subjects with advanced stage
      melanoma harbouring a BRAFV600 mutation. PET imaging and molecular diagnostics are combined
      in order to monitor response to treatment with vemurafenib plus cobimetinib, examine
      development of resistance and correlate changes in metabolic/proliferative activity with
      extend of target inhibition.