A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors

Cancer Chemother Pharmacol. 2016 Jun;77(6):1157-64. doi: 10.1007/s00280-016-3019-5. Epub 2016 Apr 12.


Purpose: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors.

Methods: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients.

Results: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition.

Conclusions: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.

Keywords: Binimetinib; Japanese; MEK inhibitor; MEK162; Phase I; Solid tumors.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Japan
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Retinal Detachment / chemically induced


  • Antineoplastic Agents
  • Benzimidazoles
  • KRAS protein, human
  • binimetinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Proto-Oncogene Proteins p21(ras)