title: Transient MEK inhibitor-associated retinopathy in metastatic melanoma.
abstract: BACKGROUND
  Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes.
  
  
  METHODS
  Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging.
  
  
  RESULTS
  Grade 1-2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography.
  
  
  CONCLUSIONS
  Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.
authors.affiliation: Private Ophthalmic Practice in Cooperation with the Skin Cancer Unit, University Hospital of Zurich, Zurich.
authors.forename: U
authors.initials: U
authors.lastname: Urner-Bloch
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich.
authors.forename: M
authors.initials: M
authors.lastname: Urner
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich.
authors.forename: P
authors.initials: P
authors.lastname: Stieger
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich.
authors.forename: N
authors.initials: N
authors.lastname: Galliker
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich.
authors.forename: N
authors.initials: N
authors.lastname: Winterton
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Zubel
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Moutouh-de Parseval
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich. Electronic address: reinhard.dummer@usz.ch.
authors.forename: R
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich.
authors.forename: S M
authors.initials: SM
authors.lastname: Goldinger
mesh_terms: D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000150:complications* / Q000473:pathology; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D012164:Retinal Diseases / Q000139:chemically induced* / Q000150:complications
chemical_list: D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases
keywords: MEK inhibition; melanoma; neuroretinal detachment; optical coherence tomography; visual disturbance