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

Carla M.L. Van Herpen, Sanjiv S. Agarwala, Axel Hauschild, Carola Berking, J. Thaddeus Beck, Dirk Schadendorf, Rob Jansen, Paola Queirolo, Paolo A. Ascierto, Christian U. Blank, Michael Heinrich, Rupam R. Pal, Adnan Derti, Victor Antona, Heidi Nauwelaerts, Angela Zubel, Reinhard Dummer

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    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 BRAFV600-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.

    Original languageEnglish (US)
    Pages (from-to)1850-1859
    Number of pages10
    JournalOncotarget
    Volume10
    Issue number19
    StatePublished - Mar 1 2019

    Fingerprint

    Melanoma
    Biomarkers
    Mitogen-Activated Protein Kinases
    Mitogen-Activated Protein Kinase Kinases
    Mutation
    MAP Kinase Kinase 1
    Neoplasms
    Gene Amplification
    MEK162
    Genes
    Disease-Free Survival
    Intercellular Signaling Peptides and Proteins
    Chromosomes
    Biopsy

    Keywords

    • Binimetinib
    • Biomarker
    • MEK inhibitor
    • Melanoma
    • Phase II

    ASJC Scopus subject areas

    • Oncology

    Cite this

    Van Herpen, C. M. L., Agarwala, S. S., Hauschild, A., Berking, C., Thaddeus Beck, J., Schadendorf, D., ... Dummer, R. (2019). Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. Oncotarget, 10(19), 1850-1859.

    Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. / Van Herpen, Carla M.L.; Agarwala, Sanjiv S.; Hauschild, Axel; Berking, Carola; Thaddeus Beck, J.; Schadendorf, Dirk; Jansen, Rob; Queirolo, Paola; Ascierto, Paolo A.; Blank, Christian U.; Heinrich, Michael; Pal, Rupam R.; Derti, Adnan; Antona, Victor; Nauwelaerts, Heidi; Zubel, Angela; Dummer, Reinhard.

    In: Oncotarget, Vol. 10, No. 19, 01.03.2019, p. 1850-1859.

    Research output: Contribution to journalArticle

    Van Herpen, CML, Agarwala, SS, Hauschild, A, Berking, C, Thaddeus Beck, J, Schadendorf, D, Jansen, R, Queirolo, P, Ascierto, PA, Blank, CU, Heinrich, M, Pal, RR, Derti, A, Antona, V, Nauwelaerts, H, Zubel, A & Dummer, R 2019, 'Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma', Oncotarget, vol. 10, no. 19, pp. 1850-1859.
    Van Herpen CML, Agarwala SS, Hauschild A, Berking C, Thaddeus Beck J, Schadendorf D et al. Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. Oncotarget. 2019 Mar 1;10(19):1850-1859.
    Van Herpen, Carla M.L. ; Agarwala, Sanjiv S. ; Hauschild, Axel ; Berking, Carola ; Thaddeus Beck, J. ; Schadendorf, Dirk ; Jansen, Rob ; Queirolo, Paola ; Ascierto, Paolo A. ; Blank, Christian U. ; Heinrich, Michael ; Pal, Rupam R. ; Derti, Adnan ; Antona, Victor ; Nauwelaerts, Heidi ; Zubel, Angela ; Dummer, Reinhard. / Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. In: Oncotarget. 2019 ; Vol. 10, No. 19. pp. 1850-1859.
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