Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advancedNRAS- orBRAF-mutated melanoma

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 BRAF V600 -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.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…None of (epi)genetic mechanisms that might influence a DUSP6 level [89,90] have been detected in our study. Moreover, assessment of pharmacodynamics effects of binimetinib (an inhibitor of MEK1/2) on MAPK signaling revealed no association of between the DUSP6 level/phosphorylation of ERK1/2 and clinical efficacy [91].…”

Primary tumor characteristics and next‐generation sequencing mutations as biomarkers for melanoma immunotherapy response

“…The NGS results in this study validate previous studies examining the impact of NRAS mutations in responders to immunotherapy. Common genetic pathway alterations found in melanoma samples from patient specimens include CDKN2A/B, PTEN, BRAF, TP53, and NRAS (van Herpen, Agarwala, & Hauschild, 2019). NRAS mutations are found in 15%–20% of melanomas and have been associated with a more aggressive phenotype and poorer outcomes compared to patients with NRAS WT melanomas (Jakob, Bassett, & Ng, 2012).…”

The Biology of Classic Hairy Cell Leukemia

“…Cytoplasmatic DUSP6 acts as another classical negative regulator of ERK activity with an absolute substrate specificity being consistently overexpressed in response to upregulated ERK signaling in BRAF-mutant melanoma [38]. Current evidence suggests a lineage specific effect and points towards a role as an oncogenic mediator in B-cells.…”