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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Study protocol

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

Authors: 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 group

Published in: BMC Cancer | Issue 1/2017

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Abstract

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.​gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
Literature
1.
Karim-Kos HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JWW. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer. 2008;44:1345–89.CrossRefPubMed
2.
3.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentral
4.
McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15:323–32.CrossRefPubMedPubMedCentral
5.
Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.CrossRefPubMed
6.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.CrossRefPubMed
7.
Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.CrossRefPubMed
8.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.CrossRefPubMedPubMedCentral
9.
Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.CrossRefPubMed
10.
Poulikakos PI, Rosen N. Mutant BRAF melanomas-dependence and resistance. Cancer Cell. 2011;19:11–5.CrossRefPubMed
11.
12.
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.CrossRefPubMed
13.
Long GV, stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.CrossRefPubMed
14.
Long GV, stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.CrossRefPubMed
15.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.CrossRefPubMed
16.
Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.CrossRefPubMed
17.
Atkinson V, Larkin J, McArthur G, Ribas A, Ascierto PA, Liszkay G, et al. Improved overall survival (OS) with cobimetinib (COBI) + vemurafenib (V) in advanced BRAF-mutated melanoma and biomarker correlates of efficacy. Society for Melanoma Research (SMR) 2015 Congress. San Francisco, California; 2015.
18.
Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s--meta-analytic comparison of PET and CT. Radiology. 1999;213:530–6.CrossRefPubMed
19.
Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med. 2003;139:879–92.CrossRefPubMed
20.
Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007:178S–201S.
21.
Ung YC, Maziak DE, Vanderveen JA, Smith CA, Gulenchyn K, Lacchetti C, et al. 18Fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review. J Natl Cancer Inst. 2007;99:1753–67.CrossRefPubMed
22.
Jiménez-Requena F, Delgado-Bolton RC, Fernández-Pérez C, Gambhir SS, Schwimmer J, Pérez-Vázquez JM, et al. Meta-analysis of the performance of 18F-FDG PET in cutaneous melanoma. Eur J Nucl Med Mol Imaging. 2009;37:284–300.CrossRefPubMed
23.
El-Maraghi R, Kiela A. PET vs sentinel lymph node biopsy for staging melanoma: a patient intervention, comparison, outcome analysis. J Am Coll Radiol. 2008;5:924–31.CrossRefPubMed
24.
Wagner T, Meyer N, Zerdoud S, Julian A, Chevreau C, Payoux P, et al. FDG PET fails to detect distant metastases at initial staging of melanoma patients with metastatic involvement of sentinel lymph node. Br J Dermat. 2011;164:1235–40.CrossRef
25.
Constantinidou A, Hofman M, O'Doherty M, Acland KM, Healy C, Harries M. Routine positron emission tomography and positron emission tomography/computed tomography in melanoma staging with positive sentinel node biopsy is of limited benefit. Melanoma Res. 2008;18:56–60.CrossRefPubMed
26.
Aukema TS, Valdés Olmos RA, Wouters MWJM, Klop WMC, Kroon BBR, Vogel WV, et al. Utility of preoperative 18F-FDG PET/CT and brain MRI in melanoma patients with palpable lymph node metastases. Ann Surg Oncol. 2010;17:2773–8.CrossRefPubMed
27.
Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, et al. Diagnostic imaging modalities for the surveillance of melanoma patients: a meta-analysis. ASCO Meeting Abstracts. 2010;28:8581.
28.
Bastiaannet E, Wobbes T, Hoekstra OS, van der Jagt EJ, Brouwers AH, Koelemij R, et al. Prospective comparison of [18F] Fluorodeoxyglucose positron emission tomography and computed tomography in patients with melanoma with palpable lymph node metastases: diagnostic accuracy and impact on treatment. J Clin Oncol. 2009;27:4774–80.CrossRefPubMed
29.
Pfannenberg C, Aschoff P, Schanz S, Eschmann SM, Plathow C, Eigentler TK, et al. Prospective comparison of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and whole-body magnetic resonance imaging in staging of advanced malignant melanoma. Eur J Cancer. 2007;43:557–64.CrossRefPubMed
30.
McArthur GA, Puzanov I, Ribas A, Chapman PB, Kim KB, Sosman JA, et al. Early FDG-PET responses to PLX4032 in BRAF-mutant advanced melanoma. ASCO Meeting Abstracts. 2010;28:8529.
31.
McArthur GA, Puzanov I, Amaravadi R, Ribas A, Chapman P, Kim KB, et al. Marked, homogeneous, and early [18F] fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma. J Clin Oncol. 2012;30:1628–34.CrossRefPubMed
32.
Søndergaard JN, Nazarian R, Wang Q, Guo D, Hsueh T, Mok S, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39.CrossRefPubMedPubMedCentral
33.
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.CrossRefPubMedPubMedCentral
34.
Baudy AR, Dogan T, Flores-Mercado JE, Hoeflich KP, Su F, van Bruggen N, et al. FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973. EJNMMI Res. 2013;2:1–10.
35.
Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43:1210–7.PubMed
36.
Been LB, Suurmeijer AJH, Cobben DCP, Jager PL, Hoekstra HJ, Elsinga PH. [18F] FLT-PET in oncology: current status and opportunities. Eur J Nucl Med Mol Imaging. 2004;31:1659–72.CrossRefPubMed
37.
Salskov A, Tammisetti V, Grierson J, Vesselle H. FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3′-deoxy-3′-[18F] fluorothymidine. Semin Nucl Med. 2007;37:429–39.CrossRefPubMed
38.
Aarntzen EHJG, Srinivas M, De Wilt JHW, Jacobs JFM, Lesterhuis WJ, Windhorst AD, et al. Early identification of antigen-specific immune responses in vivo by [18F]-labeled 3″-fluoro-3″-deoxy-thymidine ([18F] FLT) PET imaging. Proc Natl Acad Sci U S A. 2011;108:18396–9.CrossRefPubMedPubMedCentral
39.
Solit DB, Santos E, Pratilas CA, Lobo J, Moroz M, Cai S, et al. 3″-deoxy-3″-[18F] fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition. Cancer Res. 2007;67:11463–9.CrossRefPubMedPubMedCentral
40.
Leyton J, Smith G, Lees M, Perumal M, Nguyen Q-D, Aigbirhio FI, et al. Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther. 2008;7:3112–21.CrossRefPubMed
41.
McKinley ET, Smith RA, Zhao P, Fu A, Saleh SA, Uddin MI, et al. 3″-Deoxy-3″-18F-Fluorothymidine PET predicts response to V600EBRAF-targeted therapy in preclinical models of colorectal cancer. J Nucl Med. 2013;54:424–30.CrossRefPubMedPubMedCentral
42.
Geven EJW, Evers S, Nayak TK, Bergström M, Su F, Gerrits D, et al. Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of (18) F-FDG-PET and (18) F-FLT-PET. Contrast Media Mol Imaging. 2015;10:203–10.CrossRefPubMed
43.
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.CrossRefPubMedPubMedCentral
44.
Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18:683–95.CrossRefPubMedPubMedCentral
45.
Sun C, Wang L, Huang S, Heynen GJJE, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508:118–22.CrossRefPubMed
46.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.CrossRefPubMedPubMedCentral
47.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505–9.CrossRefPubMedPubMedCentral
48.
Kirkpatrick DS, Bustos DJ, Dogan T, Chan J, Phu L, Young A, et al. Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition. Proc Natl Acad Sci U S A. 2013;110:19426–31.CrossRefPubMedPubMedCentral
49.
Parker R, Clifton-Bligh R, Molloy MP. Phosphoproteomics of MAPK inhibition in BRAF-mutated cells and a role for the lethal synergism of dual BRAF and CK2 inhibition. Mol Cancer Ther. 2014;13:1894–906.CrossRefPubMed
50.
Fedorenko IV, Fang B, Munko AC, Gibney GT, Koomen JM, Smalley KSM. Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma. Proteomics. 2015;15:327–39.CrossRefPubMed
51.
Stuart SA, Houel S, Lee T, Wang N, Old WM, Ahn NG. A Phosphoproteomic comparison of B-RAFV600E and MKK1/2 inhibitors in melanoma cells. Mol Cell Proteomics. 2015;14:1599–615.CrossRefPubMedPubMedCentral
52.
Fedorenko IV, Abel EV, Koomen JM, Fang B, Wood ER, Chen YA, et al. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene. 2016;35:1225–35.CrossRefPubMed
53.
Boellaard R. Standards for PET image acquisition and quantitative data analysis. J Nucl Med. 2009;50:11S–20S.CrossRefPubMed
54.
Boellaard R, Hoekstra OS, Lammertsma AA. Software tools for standardized analysis of FDG whole body studies in multi- center trials. J Nucl Med. 2008;49:159P.
55.
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.CrossRefPubMedPubMedCentral
56.
Larkin J, Yan Y, McArthur GA. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33:9006S.
57.
Dobbin KK, Simon RM. Sample size planning for developing classifiers using high-dimensional DNA microarray data. Biostatistics. 2006;8:101–17.CrossRefPubMed
58.
Altman DG, Bland JM. Measurement in medicine: the analysis of method comparison studies. Underst Stat. 1983;32:307–17.
59.
Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1:307–10.CrossRefPubMed
60.
Heagerty PJ, Zheng Y. Survival model predictive accuracy and ROC curves. Biometrics. 2005;61:92–105.CrossRefPubMed
Metadata
Title
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
Authors
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 group
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3626-5

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