Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: Response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study

Bernies van der Hiel*, John B. A. G. Haanen, Marcel P. M. Stokkel, Daniel S. Peeper, Connie R. Jimenez, Jos H. Beijnen, Bart A. van de Wiel, Ronald Boellaard, Alfons J. M. van den Eertwegh, REPOSIT Study Grp

*Corresponding author for this work

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BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment.

Molecular imaging with F-18-Fluorodeoxyglucose (F-18-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of F-18-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. F-18-Fluoro-3'-deoxy-3' L-fluorothymidine (F-18-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than F-18-FDG.

METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by F-18-FDG/F-18-FLT PET can predict progression-free survival and whether early changes in F-18-FDG/F-18-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks.

Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo F-18-FDG PET/CT and in 25 patients additional F-18-FLT PET/CT is performed.

Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance.

Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.

DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both F-18-FDG and F-18-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment.

Original languageEnglish
Article number649
Number of pages13
JournalBMC Cancer
Publication statusPublished - 15-Sep-2017


  • Stage IIIc/IV melanoma
  • Resistance
  • BRAF inhibitor
  • MEK inhibitor
  • F-18-FDG
  • F-18-FLT
  • PET/CT

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