title: MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects.
abstract: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition.
  
  
  
  In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria.
  
  
  
  Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity.
  
  
  
  Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.
authors: Private Ophthalmic Practice in Cooperation with the Skin Cancer Unit, University Hospital of Zurich, Zurich, Switzerland.
authors: U
authors: U
authors: Urner-Bloch
authors: Medical Intensive Care Unit, University Hospital Zurich, Zurich, Switzerland; Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors: M
authors: M
authors: Urner
authors: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
authors: N
authors: N
authors: Jaberg-Bentele
authors: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
authors: A L
authors: AL
authors: Frauchiger
authors: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. Electronic address: reinhard.dummer@usz.ch.
authors: R
authors: R
authors: Dummer
authors: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
authors: S M
authors: SM
authors: Goldinger
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001562:Benzimidazoles / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012164:Retinal Diseases / Q000139:chemically induced*; D012878:Skin Neoplasms / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C581313:binimetinib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: BRAF inhibition; Long-term treatment; MEK inhibition; Melanoma; Optical coherence tomography; Retinopathy