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2 Inhibitor Binimetinib (Mek162) in Patients with Advanced Nras-Mutant Melanoma
Annals of Oncology 25 (Supplement 5): v1–v41, 2014 doi:10.1093/annonc/mdu438.43
Knight Cancer Institute, Oregon, OR, USA LBA35
OVERALL SURVIVAL AND BIOMARKER RESULTS FROM A PHASE 2 STUDY OF MEK1/2 INHIBITOR BINIMETINIB (MEK162) IN PATIENTS WITH ADVANCED NRAS-MUTANT MELANOMA
abstracts
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 23, 2015
C. van Herpen1, S.S. Agarwala2, A. Hauschild3, R. Dummer4, C. Berking5, J. T. Beck6, D. Schadendorf7, G. Gibney8, R. Jansen9, P. Queirolo10, P.A. Ascierto11, C. Blank12, H. Nauwelaerts13, F. Niazi13, R.R. Pal14, A. Reddy15, V. Antona13, A. Zubel13, M.C. Heinrich16 1 Department of Medical Oncology/452, Radboud University Medical Centre Nijmegen, Nijmegen, NETHERLANDS 2 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, PA, USA 3 Dept. of Dermatology, Universitätsklinikum Schleswig-Holstein, Kiel, GERMANY 4 Department of Dermatology, University Hospital of Zurich, Zurich, SWITZERLAND 5 Dermatology, University of Munich, Munich, GERMANY 6 Highlands Oncology Group, Fayetteville, AR, USA 7 Dermatology, University Hospital Essen, Essen, GERMANY 8 Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA 9 Medical Oncology, Maastricht University Medical Center (MUMC), Maastricht, NETHERLANDS 10 Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, ITALY 11 Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, ITALY 12 Medical Oncology, The Netherlands Cancer Institute, Amsterdam, NETHERLANDS 13 Translational Medicine, Novartis Pharma AG, Basel, SWITZERLAND 14 Oncology, Novartis Healthcare Pvt. Ltd., Hyderabad, INDIA 15 Oncology, Novartis Pharmaceuticals Corporation, Boston, MA, USA 16 Portland VA Medical Center, Oregon Health & Science University and OHSU
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.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Knight Cancer Institute, Oregon, OR, USA LBA35
OVERALL SURVIVAL AND BIOMARKER RESULTS FROM A PHASE 2 STUDY OF MEK1/2 INHIBITOR BINIMETINIB (MEK162) IN PATIENTS WITH ADVANCED NRAS-MUTANT MELANOMA
abstracts
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 23, 2015
C. van Herpen1, S.S. Agarwala2, A. Hauschild3, R. Dummer4, C. Berking5, J. T. Beck6, D. Schadendorf7, G. Gibney8, R. Jansen9, P. Queirolo10, P.A. Ascierto11, C. Blank12, H. Nauwelaerts13, F. Niazi13, R.R. Pal14, A. Reddy15, V. Antona13, A. Zubel13, M.C. Heinrich16 1 Department of Medical Oncology/452, Radboud University Medical Centre Nijmegen, Nijmegen, NETHERLANDS 2 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, PA, USA 3 Dept. of Dermatology, Universitätsklinikum Schleswig-Holstein, Kiel, GERMANY 4 Department of Dermatology, University Hospital of Zurich, Zurich, SWITZERLAND 5 Dermatology, University of Munich, Munich, GERMANY 6 Highlands Oncology Group, Fayetteville, AR, USA 7 Dermatology, University Hospital Essen, Essen, GERMANY 8 Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA 9 Medical Oncology, Maastricht University Medical Center (MUMC), Maastricht, NETHERLANDS 10 Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, ITALY 11 Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, ITALY 12 Medical Oncology, The Netherlands Cancer Institute, Amsterdam, NETHERLANDS 13 Translational Medicine, Novartis Pharma AG, Basel, SWITZERLAND 14 Oncology, Novartis Healthcare Pvt. Ltd., Hyderabad, INDIA 15 Oncology, Novartis Pharmaceuticals Corporation, Boston, MA, USA 16 Portland VA Medical Center, Oregon Health & Science University and OHSU
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.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].