Oncotarget

Research Papers:

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 C. Heinrich, Rupam R. Pal, Adnan Derti, Victor Antona, Heidi Nauwelaerts, Angela Zubel and Reinhard Dummer

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Oncotarget. 2019; 10:1850-1859. https://doi.org/10.18632/oncotarget.26753

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Abstract

Carla M.L. van Herpen1, Sanjiv S. Agarwala2, Axel Hauschild3, Carola Berking4, J. Thaddeus Beck5, Dirk Schadendorf6, Rob Jansen7, Paola Queirolo8, Paolo A. Ascierto9, Christian U. Blank10, Michael C. Heinrich11, Rupam R. Pal12, Adnan Derti13, Victor Antona14, Heidi Nauwelaerts14, Angela Zubel14 and Reinhard Dummer15

1Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands

2Department of Medical Oncology and Hematology, St. Luke's University Health Network, Bethlehem, PA, USA

3Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany

4Department of Dermatology, University Hospital of Munich (LMU), Munich, Germany

5Department of Oncology, Highlands Oncology Group, Fayetteville, AR, USA

6Department of Dermatology, University Hospital Essen, Essen, Germany

7Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands

8Department of Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

9Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy

10Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

11Department of Medicine, Veterans Administration Portland Health Care System and Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA

12Biostatistics, Novartis Healthcare Private Limited, Hyderabad, India

13Department of Translational Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

14Department of Translational Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland

15Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

Correspondence to:

Carla M.L. van Herpen, email: Carla.vanHerpen@radboudumc.nl

Keywords: binimetinib; MEK inhibitor; biomarker; melanoma; phase II

Received: August 24, 2017     Accepted: February 09, 2019     Published: March 05, 2019

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.


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