LBA35 - Overall survival and biomarker results from a phase 2 study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS-mutant melanoma

Date 29 September 2014
Event ESMO 2014
Session Melanoma and other skin tumours
Topics Anti-Cancer Agents & Biologic Therapy
Melanoma and other Skin Tumours
Translational Research
Presenter Carla van Herpen
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors 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
  • 1Department Of Medical Oncology/452, Radboud University Medical Centre Nijmegen, 6500 HB - Nijmegen/NL
  • 2Cancer Center, St. Luke's Hospital & Health Network, 18015 - Bethlehem/US
  • 3Dept. Of Dermatology, Universitätsklinikum Schleswig-Holstein, Kiel/DE
  • 4Department Of Dermatology, University Hospital of Zurich, Zurich/CH
  • 5Dermatology, University of Munich, Munich/DE
  • 6Highlands Oncology Group, Highlands Oncology Group, Fayetteville/US
  • 7Dermatology, University Hospital Essen, 45122 - Essen/DE
  • 8Cutaneous Oncology, Moffitt Cancer Center, Tampa/US
  • 9Medical Oncology, Maastricht University Medical Center (MUMC), Maastricht/NL
  • 10Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa/IT
  • 11Unit Of Medical Oncology And Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Naples/IT
  • 12Medical Oncology, The Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 13Translational Medicine, Novartis Pharma AG, Basel/CH
  • 14Oncology, Novartis Healthcare Pvt. Ltd., Hyderabad/IN
  • 15Oncology, Novartis Pharmaceuticals Corporation, Boston/US
  • 16Portland Va Medical Center, Oregon Helath & Science University and OHSU Knight Cancer Institute, 97239 - Oregon/US

 

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.

Disclosure

C. van Herpen: has been on a board of directors and/or advisory board for Merck and has received research funding for Novartis and Merck; A. Hauschild: has received trial grants for Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD, Novartis, Oncosec, Roche. He has also consulted for and received honoraria from these companies and MedImmune; R. Dummer: has received research funding and consulted for Novartis; C. Berking: has consulted for Novartis, Roche, GSK, MSD, BMS, Astrazenca; received honoraria from Novartis, Roche, GSK, MSD, BMS; J.T. Beck: has received research funding from Novartis; D. Schadendorf: has been on a board of directors and/or advisory board, consulted for, and received honoraria from Novartis, GSK, Roche, BMS, Merck, Amgen; received research funding from Merck; G. Gibney: has been on a board of directors and/or advisory committee for and consulted for Genentech/Roche; P. Queirolo: has been on a board of directors and/or advisory committee for Roche, GSK, BMS; has consulted for Roche; received honoraria from GSK; P.A. Ascierto: received research funding from Novartis, Roche-Genentech, Ventana; been on a BOD or advisory committee for Novartis, Roche-Genentech, GSK, BMS; consulted for Roche-Genentech, MSD, GSK, Ventana, received honoraria from BMS, Roche-Genentech, GSK; C. Blank: has received research funding from Novartis and has been on a board of directors and/or advisory committee for Novartis, Roche, BMS, GSK, MSD; H. Nauwelaerts, F. Niazi, V. Antona and A. Zubel: is an employee of Novartis Pharma AG; R.R. Pal: is an employee of Novartis Healthcare Pvt. Ltd.; A. Reddy: is an employee of Novartis Pharmaceuticals Corporation; M.C. Heinrich: has received research funding from Novartis, Pfizer, Ariad, AROG; consulted for Novartis, Pfizer, Ariad, MolecularMD; received honoraria from Novartis, Pfizer, Ariad; owned stock in MolecularMD; provided expert testimony for Novartis. All other authors have declared no conflicts of interest.