Overall Survival and Biomarker Results from a Phase 2 Study of Mek1/2 Inhibitor Binimetinib (Mek162) in Patients with Advanced Nras-Mutant Melanoma

Abstract

Aim No approved therapies exist that specifically target NRAS-mutant melanoma (≈ 20% of cases). In this study of BRAF V600- or NRAS-mutant melanoma, binimetinib, a potent and selective MEK1/2 inhibitor, was the first targeted therapy to show preliminary clinical activity in NRAS-advanced melanoma (Ascierto et al. Lancet Oncol, 2013). Methods This is a phase 2 open-label single arm study of binimetinib 45 mg orally twice daily (bid) in patients with advanced/unresectable or metastatic BRAF V600- or NRAS-mutant melanoma. Updated efficacy, safety, and biomarker analyses of a larger NRAS-mutant subgroup than previously reported are presented here. Primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival (PFS) and overall survival (OS). Genomic profiling covering a panel of 293 clinically relevant cancer genes was conducted on pretreatment biopsies. Results Patients with NRAS-mutant melanoma (n = 117) received binimetinib 45 mg bid. Median duration of exposure was 15.9 wks. ORR was 14.5% (1 CR, 16 PRs); disease control rate (≥SD) was 56%. Median PFS was 3.6 mos (95% CI, 2.6–3.8); median OS was 12.2 mos (Lower 95% CI, 7.9). The most common treatment-related adverse events (AEs) were dermatitis acneiform (54%), increased blood creatine phosphokinase (CK, 51%), and peripheral edema (42%). The most common grade 3/4 AE was increased blood CK (25%). Reduced pERK and DUSP6 expression demonstrated MAPK pathway inhibition by binimetinib; however, there was no clear association between efficacy and reduced expression, maybe due to limited data. Genetic landscape of a subset of patients (n = 78) with corresponding efficacy will be presented. CCND1 or CCND3 amplifications were exclusively seen in 5 patients with shorter PFS (≤3.6 mos), suggesting the hypothesis that constitutive CDK4/6 pathway signaling may play a role in resistance. Conclusions Binimetinib 45mg bid is active in NRAS-mutant melanoma with an acceptable safety profile. A pivotal phase 3 study (NEMO) evaluating binimetinib in NRAS-mutant melanoma is ongoing. Understanding of the genetic landscape will be further refined from data collected in the NEMO study.