TY - JOUR
T1 - Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma
T2 - Response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): Study protocol of a phase II, open-label, multicenter study
AU - van der Hiel, Bernies
AU - Haanen, John B A G
AU - Stokkel, Marcel P M
AU - Peeper, Daniel S.
AU - Jimenez, Connie R.
AU - Beijnen, Jos H
AU - van de Wiel, Bart A.
AU - Boellaard, Ronald
AU - van den Eertwegh, Alfons J M
AU - van Tinteren, H.
AU - Wessels, Lodewyk F A
AU - Lolkema, Martijn P J K
AU - Hoekstra, Otto S
AU - Hospers, Geke A P
AU - Brouwers, Adrienne H
AU - Koornstra, R.H.T.
AU - Arens, A. I. J.
AU - de Vos, F. Y.F.L.
AU - Hobbelink, M. G.G.
AU - Kapiteijn, H. W.
AU - de Geus-Oei, L. F.
AU - Kruit, W. H.J.
AU - Verzijlbergen, F.J.
AU - Aarts, M. J.B.
AU - Mottaghy, F. M.
AU - de Groot, J. W.B.
AU - Knollema, S.
AU - Piersma, D.
AU - Agool, A.
AU - Vreugdenhil, Art
AU - Liem, I H
AU - van den Berkmortel, Franchette W P J
AU - Schreurs, M.W.
N1 - Funding Information:
This study is supported by an unrestricted grant by Roche Medical B.V. The company has approved the design of the study and provided cobimetinib free of charge. The company has no role in collection, analysis, and interpretation of data or in writing the manuscript.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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 18F-Fluorodeoxyglucose (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 uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-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 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-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 18F-FDG PET/CT and in 25 patients additional 18F-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 18F-FDG and 18F-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. Trial registration:Clinicaltrials.govidentifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
AB - 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 18F-Fluorodeoxyglucose (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 uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-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 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-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 18F-FDG PET/CT and in 25 patients additional 18F-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 18F-FDG and 18F-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. Trial registration:Clinicaltrials.govidentifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
KW - F-FDG
KW - F-FLT
KW - BRAF inhibitor
KW - MEK inhibitor
KW - PET/CT
KW - Resistance
KW - Stage IIIc/IV melanoma
KW - Sulfonamides/administration & dosage
KW - Melanoma/diagnostic imaging
KW - Azetidines/administration & dosage
KW - Piperidines/administration & dosage
KW - Skin Neoplasms/diagnostic imaging
KW - Humans
KW - Drug Resistance, Neoplasm
KW - Treatment Outcome
KW - Positron-Emission Tomography
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Indoles/administration & dosage
KW - Disease-Free Survival
KW - Vemurafenib
KW - Multicenter Studies as Topic
KW - Neoplasm Staging
KW - Research Design
KW - Clinical Trials, Phase II as Topic
UR - http://www.scopus.com/inward/record.url?scp=85029527710&partnerID=8YFLogxK
U2 - 10.1186/s12885-017-3626-5
DO - 10.1186/s12885-017-3626-5
M3 - Article
C2 - 28915798
AN - SCOPUS:85029527710
SN - 1471-2407
VL - 17
SP - 1
EP - 10
JO - BMC Cancer
JF - BMC Cancer
IS - 1
M1 - 649
ER -