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.
Highlights
The mitogen-activated protein kinase (MAPK) signaling pathway (i.e., RAS-RAFMEK-ERK pathway) regulates cellular proliferation, survival, and differentiation and contributes to the pathogenesis of melanoma [1]
A number of therapies that directly target the MAPK pathway have been approved for BRAF-mutated melanoma, including the BRAFV600- specific inhibitors vemurafenib, and dabrafenib, and mitogenactivated protein kinase (MEK) inhibitors trametinib and cobimetinib [9,10,11,12,13,14,15]
Biomarker results presented are derived from the later cut-off date
Summary
The MAPK signaling pathway (i.e., RAS-RAFMEK-ERK pathway) regulates cellular proliferation, survival, and differentiation and contributes to the pathogenesis of melanoma [1]. Multiple genetic changes can lead to hyperactivation of this pathway, and are involved in the pathogenesis of various solid tumor types, including melanoma and thyroid, colorectal, and ovarian cancer [2,3,4,5]. Constitutive MAPK pathway activation in cancer can occur through several mechanisms, most frequently via mutations in BRAF or RAS. A number of therapies that directly target the MAPK pathway have been approved for BRAF-mutated melanoma, including the BRAFV600- specific inhibitors vemurafenib (single agent), and dabrafenib (single agent or in combination with trametinib), and mitogenactivated protein kinase (MEK) inhibitors trametinib (single agent or in combination with dabrafenib) and cobimetinib (in combination with vemurafenib) [9,10,11,12,13,14,15]. In addition to the nonspecific immunotherapies, three immune checkpoint modulators, ipilimumab (anticytotoxic T-lymphocyte associated antigen 4 [CTLA-4]), nivolumab (anti–programmed cell death protein 1 [PD-1]), and pembrolizumab (anti–PD-1), have been approved for the treatment of melanoma [19]
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