MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

Duncan, Katherine; Chang, Luke; Patronas, Marena

doi:10.1038/eye.2015.82

Cited by 71 publications

(65 citation statements)

References 23 publications

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“…Furthermore, 77% of patients on MEK inhibition had multifocal fluid foci, with a median number of 6 foci per eye. This confirms the findings of other reports that have shown bilateral, multifocal serous elevations typically with subfoveal involvement 6–8,10–12 . Despite only 48% of patients reporting visual symptoms, 83% of eyes in this study had fluid foci involving the fovea.…”

Section: Discussionsupporting

confidence: 92%

Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy

et al. 2017

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Purpose To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking Mitogen-activated protein kinase kinase (MEK)-inhibitors. Participants 313 fluid foci in 50 eyes of 25 patients receiving MEK-inhibitors for treatment of their metastatic cancer, whom had evidence of serous retinal detachments confirmed by optical coherence tomography(OCT). Design Single center, retrospective, cohort study Methods Clinical exam and OCT were used to evaluate MEK-inhibitor associated subretinal fluid. The morphology, distribution and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate inter-observer findings, compare choroidal thickness and visual acuity at each time point. Main Outcom1e Measures Comparison of OCT characteristcs of retinal abnormalities at baseline to fluid accumulation. Results The majority of patients had fluid foci that were bilateral (92%), multifocal (77%) and at least one focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into four morphologies as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than two Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation and fluid resolution). A strong positive inter-observer correlation was obtained for choroidal thickness measurements (r=0.97, p<0.0001) and grading of foci morphology (r=0.97, p<0.0001). Conclusion The subretinal fluid foci associated with MEK-inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK-inhibitors did not cause irreversible loss of vision or serious eye damage.

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Section: Discussionsupporting

confidence: 92%

Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy

et al. 2017

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“…However, drug-related adverse events typical for MEK inhibitors, including retinal events, persist [8][9][10]. Some clinical features of MEK inhibitor-associated retinopathy, resembling to the well-known central serous chorioretinopathy [16], have been described in two studies with about 30 patients and in three small case series [15,[17][18][19][20]. At present, no long-term data is available.…”

Section: Introductionmentioning

confidence: 99%

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

Urner-Bloch

Urner

Jaberg-Bentele

et al. 2016

European Journal of Cancer

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BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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“…A pathophysiological mechanism for the ophthalmic toxicity of MEK inhibitors has been hypothesized [14,26]. Most of the ocular events reported under MEK inhibitor treatment occurred in the retina, with subretinal fluid accumulation (without retinal vein occlusion) being frequently found in such patients.…”

Section: Discussionmentioning

confidence: 99%

“…To patients about to start chemotherapy using MEK inhibitors, a baseline retinal examination should be recommended, as well as close ophthalmic monitoring, in particular during the first year of treatment [14]. Summaries of the product characteristics of both trametinib and cobimetinib recommend health care professionals to conduct prompt ophthalmological assessments if patients report new visual disturbances such as diminished central vision, blurry vision, or loss of vision while on therapy with MEK inhibitors [30,31].…”

Section: Discussionmentioning

confidence: 99%

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Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis

et al. 2016

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Objectives: This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. Methods: A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I² statistics. Results: Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p < 0.0001; I² = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p < 0.0001; I² = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p < 0.0001; I² = 0%), and blurred vision (OR 2.30; 95% CI 1.50-3.54; p < 0.0001; I² = 60.1%), but not for uveitis (OR 0.99; 95% CI 0.14-7.03; p = 0.991; I² = 2.9%) or eye haemorrhage (OR 0.72; 95% CI 0.04-12.39; p = 0.824; I² = 29.8%). Conclusions: Treatment with MEK inhibitors seems to increase the risk of ophthalmic adverse effects. A need for monitoring the safety of this class of drugs exists. Regulators, clinicians, and other health care professionals must, together, be involved in this process.

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MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

Cited by 71 publications

References 23 publications

Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy

Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis

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