Abstract
BackgroundIn 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.MethodsThis 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.DiscussionThe 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 registrationClinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
Highlights
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 progressionfree survival and overall survival compared to treatment with vemurafenib alone
On May 29, 2013, BRAF inhibitor dabrafenib was approved by the Food and Drug Administration (FDA), based on demonstration of improved Progression-free survival (PFS) in a phase III multi-center, international, open-label, randomized controlled trial [9]
Study objectives The primary aims of this study are to evaluate whether changes in 18F-FDG and/or 18F-FLT Positron emission tomography (PET) in the first 7 weeks can predict progression-free survival and whether early changes in 18F-FDG and/or 18F-FLT PET can be used for early detection of response to treatment with combined BRAF/MEK inhibitor vemurafenib plus cobimetinib compared to standard response assessment with contrast enhanced CT (ceCT) according to Response evaluation criteria in solid tumors (RECIST) v1.1 at 7 weeks
Summary
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 progressionfree survival and overall survival compared to treatment with vemurafenib alone. The only available systemic therapy was the chemotherapeutic agent dacarbazine, resulting in poor response rates (around 5–20%) and no significant survival benefit. This changed in 2011 with the introduction of the immune checkpoint inhibitor ipilimumab and inhibitor of the MAP kinase pathway vemurafenib, anti-melanoma agents that improved progression free and overall survival of patients with advanced melanoma [3, 4]. What is the optimal sequence of immunotherapy and targeted therapy? Second, can we predict and overcome resistance against these agents?
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