1. Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma
- Author
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van der Hiel, Bernies, Haanen, John B A G, Stokkel, Marcel P M, Peeper, Daniel S., Jimenez, Connie R., Beijnen, Jos H, van de Wiel, Bart A., Boellaard, Ronald, van den Eertwegh, Alfons J M, van Tinteren, H., Wessels, Lodewyk F A, Lolkema, Martijn P J K, Hoekstra, Otto S, Hospers, Geke A P, Brouwers, Adrienne H, Koornstra, R.H.T., Arens, A. I. J., de Vos, F. Y.F.L., Hobbelink, M. G.G., Kapiteijn, H. W., de Geus-Oei, L. F., Kruit, W. H.J., Verzijlbergen, F.J., Aarts, M. J.B., Mottaghy, F. M., de Groot, J. W.B., Knollema, S., Piersma, D., Agool, A., Vreugdenhil, Art, Liem, I H, van den Berkmortel, Franchette W P J, Schreurs, M.W., Guided Treatment in Optimal Selected Cancer Patients (GUTS), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), AGEM - Re-generation and cancer of the digestive system, Medical oncology laboratory, CCA - Cancer Treatment and quality of life, and Medical oncology
- Subjects
0301 basic medicine ,Oncology ,Pathology ,Cancer Research ,Indoles ,Skin Neoplasms ,medicine.medical_treatment ,Resistance ,Targeted therapy ,BRAF-MUTATED MELANOMA ,chemistry.chemical_compound ,Study Protocol ,0302 clinical medicine ,Piperidines ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,METASTATIC MELANOMA ,Multicenter Studies as Topic ,Vemurafenib ,Stage IIIc/IV melanoma ,Melanoma ,IN-VIVO ,Sulfonamides ,medicine.diagnostic_test ,IMPROVED SURVIVAL ,MEK inhibitor ,RANDOMIZED CONTROLLED-TRIAL ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Treatment Outcome ,Positron emission tomography ,Research Design ,030220 oncology & carcinogenesis ,medicine.drug ,F-FLT ,BRAF inhibitor ,medicine.medical_specialty ,PET/CT ,CELL LUNG-CANCER ,F-FDG ,lcsh:RC254-282 ,Disease-Free Survival ,F-18-FDG ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,Internal medicine ,Genetics ,Journal Article ,Humans ,Stage IIIC ,F-18-FLT ,MEK INHIBITION ,LYMPH-NODE ,Neoplasm Staging ,Cobimetinib ,PET-CT ,business.industry ,MUTATIONS ,medicine.disease ,MUTANT MELANOMA ,18F-FDG ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Positron-Emission Tomography ,18F-FLT ,Azetidines ,business - Abstract
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. 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. 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. Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
- Published
- 2017