Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma.

Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma.

Publication date: Mar 05, 2019

BRAF and RAS are the most frequently mutated mitogen-activated protein kinase (MAPK) genes in melanoma. Binimetinib is a highly selective MAPK kinase (MEK) 1/2 inhibitor with clinical antitumor activity in NRAS- and BRAF-mutant melanoma. We performed a nonrandomized, open-label phase II study, where 183 metastatic melanoma patients received binimetinib 45 mg / 60 mg twice-daily (BRAF arms), or binimetinib 45 mg twice-daily (NRAS arm). Biomarker analyses were prespecified as secondary and exploratory objectives. Here we report the extent of MAPK pathway inhibition by binimetinib, genetic pathway alterations of interest, and potential predictive markers for binimetinib efficacy. Twenty-five fresh pre- and post-dose tumor sample pairs were collected for biomarker analyses, which included assessment of binimetinib on MEK/MAPK signaling by pharmacodynamic analysis of pERK and DUSP6 expression in pre- vs post-dose tumor biopsies; identification of pERK and DUSP6 expression/efficacy correlations; assessment of baseline tumor molecular status; and exploration of potential predictive biomarkers of efficacy of binimetinib. The postbaseline pERK and DUSP6 expression decreased across all arms; no association between reduced pERK or DUSP6 levels with clinical efficacy was observed. Genetic aberrations were similar to previously reported data on clinical melanoma samples. Genetic pathway alterations occurred predominantly within CDKN2A/B, PTEN, and TRRAP (BRAF-mutation) and CDKN2A/B, TP53, and NOTCH2 (NRAS-mutation). Several patients with BRAF mutations had amplification of genes on chromosome 7q; these patients tended to have shorter progression-free survival than other patients with BRAF-mutant melanoma. Further analysis of genetic alterations, including amplifications of growth factor genes, will determine utility as biomarkers for efficacy.

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van Herpen, C.M.L., Agarwala, S.S., Hauschild, A., Berking, C., Beck, J.T., Schadendorf, D., Jansen, R., Queirolo, P., Ascierto, P.A., Blank, C.U., Heinrich, M.C., Pal, R.R., Derti, A., , Antona, Nauwelaerts, H., Zubel, A., and Dummer, R. Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. 22355. 2019 Oncotarget (10):19.

Concepts Keywords
Aberrations Melanoma
Biomarker Mitogen-activated protein kinase
Biomarkers BRAF
Biopsies Melanoma
BRAF CDKN2A
CDKN2A MEK inhibitor
Chromosome Binimetinib
Genetic Organobromides
Genetic Pathway Biomarkers
Growth Factor Benzamides
Inhibitor Branches of biology
Kinase Clinical medicine
MAPK Medicine
MAPK Kinase Assessment baseline tumor
MEK Clinical melanoma
Melanoma
Mitogen
Mutant
Mutation
Pharmacodynamic
PTEN
RAS
TP53
Tumor

Semantics

Type Source Name
gene UNIPROT BCR
disease DOID CML
disease DOID CML
gene UNIPROT GLI1
pathway BSID Apoptosis
gene UNIPROT BRD2
disease DOID biliary tract cancer
disease MESH biliary tract cancer
gene UNIPROT DUOXA1
gene UNIPROT HRAS
gene UNIPROT KRAS
gene UNIPROT AOC2
gene UNIPROT TSC1
gene UNIPROT TSC2
gene UNIPROT GOPC
gene UNIPROT FBLIM1
disease MESH clonal evolution
drug DRUGBANK Guanosine
gene UNIPROT FNDC3A
drug DRUGBANK (S)-Des-Me-Ampa
gene UNIPROT EXOG
gene UNIPROT CXCL2
disease MESH metastases
drug DRUGBANK Bismuth subgallate
disease DOID cutaneous melanoma
gene UNIPROT MTOR
gene UNIPROT AKT1
gene UNIPROT COL9A3
gene UNIPROT COMP
gene UNIPROT COL9A1
gene UNIPROT COL9A2
gene UNIPROT SCN8A
gene UNIPROT PMCH
drug DRUGBANK Methacholine
gene UNIPROT SPEN
drug DRUGBANK Etoperidone
gene UNIPROT RHBDL1
gene UNIPROT RRBP1
disease DOID cancer
drug DRUGBANK Formaldehyde
gene UNIPROT DUSP5
gene UNIPROT LAT2
disease MESH tachycardia
disease DOID cardiomyopathy
disease MESH cardiomyopathy
disease MESH acute liver failure
gene UNIPROT COL4A2
disease MESH ICH
drug DRUGBANK Encorafenib
gene UNIPROT COL17A1
drug DRUGBANK Ribociclib
gene UNIPROT CDK4
gene UNIPROT SMO
gene UNIPROT SMOX
gene UNIPROT EZH2
gene UNIPROT HGF
gene UNIPROT IL6
gene UNIPROT SOS1
gene UNIPROT RNMT
gene UNIPROT MET
gene UNIPROT SLTM
drug DRUGBANK Methionine
gene UNIPROT SLC25A16
disease MESH genetic markers
gene UNIPROT MAGEE1
gene UNIPROT PIK3CG
gene UNIPROT PIK3CB
gene UNIPROT PIK3CD
gene UNIPROT PIK3CA
gene UNIPROT CCND3
gene UNIPROT CCND1
gene UNIPROT CDKN2B
gene UNIPROT DCXR
disease MESH liver failure
gene UNIPROT HELT
gene UNIPROT UNK
gene UNIPROT CDCA8
gene UNIPROT EYA1
disease DOID BOR
gene UNIPROT BID
gene UNIPROT ATP8A2
drug DRUGBANK ATP
gene UNIPROT IKBKG
drug DRUGBANK Dacarbazine
drug DRUGBANK Pembrolizumab
disease MESH death
drug DRUGBANK Nivolumab
drug DRUGBANK Ipilimumab
drug DRUGBANK Cobimetinib
drug DRUGBANK Trametinib
drug DRUGBANK Dabrafenib
drug DRUGBANK Vemurafenib
disease MESH Multiple
gene UNIPROT EPHB2
gene UNIPROT ZHX2
gene UNIPROT MAPK1
pathway BSID MAPK signaling pathway
pathway BSID MAPK Signaling Pathway
drug DRUGBANK Coenzyme M
pathway BSID Reproduction
gene UNIPROT CEP55
gene UNIPROT NAA50
gene UNIPROT TNIP1
disease MESH growth
gene UNIPROT NOTCH2
gene UNIPROT TP53
gene UNIPROT TRRAP
gene UNIPROT PTEN
gene UNIPROT CDKN2A
gene UNIPROT DUSP6
gene UNIPROT EIF2AK3
disease MESH tumor
gene UNIPROT SLC35G1
gene UNIPROT ARMC9
gene UNIPROT AKR1A1
gene UNIPROT KIDINS220
gene UNIPROT MAP2K7
drug DRUGBANK Rasagiline
pathway BSID Melanoma
disease MESH melanoma
disease DOID melanoma
gene UNIPROT BRAF
gene UNIPROT NRAS
drug DRUGBANK Binimetinib
gene UNIPROT MAP2K1

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