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Original Investigation | Journal Club

Subretinal Fluid Associated With MEK Inhibitor Use in the Treatment of Systemic Cancer

Marissa L. Weber, MD1,2; Michelle C. Liang, MD1,3; Keith T. Flaherty, MD4; Jeffrey S. Heier, MD1
[+] Author Affiliations
1Ophthalmic Consultants of Boston, Boston, Massachusetts
2Ophthalmology Service, Walter Reed National Military Medical Center, Bethesda, Maryland
3New England Eye Center, Tufts Medical Center, Boston, Massachusetts
4Department of Medicine, Massachusetts General Hospital, Boston
JAMA Ophthalmol. 2016;134(8):855-862. doi:10.1001/jamaophthalmol.2016.0090.
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Importance  The use of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors has become more common in the treatment of systemic cancer. These agents have been associated with a central serous-like retinopathy in some patients. Recognition of such retinal findings and the relatively benign nature of these events is important to avoid unnecessary intervention, including the cessation of a potentially life-prolonging medication.

Objectives  To evaluate the presence and characteristics of subretinal fluid (SRF) associated with the use of MEK inhibitors in the treatment of systemic cancer and to correlate the presence of SRF with visual acuity and symptoms over time.

Design, Setting, and Participants  Post hoc analysis was conducted of prospectively collected data from 51 patients with locally advanced or metastatic cancer undergoing treatment with the MEK inhibitor binimetinib in 1 of 4 clinical trials. All clinical trial participants underwent complete ophthalmic examination by retina specialists at a private practice in Boston, Massachusetts, and were monitored between February 29, 2012, and January 8, 2014. The examination included Snellen-measured visual acuity, dilated fundus examination, and spectral-domain optical coherence tomography at baseline, biweekly for 2 months, then monthly for the remainder of their trial participation. Post hoc design and data analysis were performed between December 1, 2013, and June 20, 2014.

Main Outcomes and Measures  Visual symptoms, visual acuity, fundus appearance, and the presence and characteristics of SRF noted on optical coherence tomography. The characteristics of angiograms performed at the discretion of the treating physician were reviewed.

Results  Of the 51 participants, 18 (35%) were men; the mean (SD) age was 60 (13) years (range, 32-87 years). Forty-six (90%) study participants developed SRF during the study period, with 9 (20%) experiencing symptoms at any point. The mean (SD) central retinal thickness of 39 study participants who developed SRF at the first visit increased from 280 (26) µm at baseline to 316 (43) µm at the first visit after starting binimetinib treatment (paired t test, P < .001). On examination, SRF appeared as elevated, yellow-orange pockets in the fovea and/or along the arcades. Corresponding optical coherence tomographic imaging revealed SRF beneath the interdigitation zone. The fovea was affected in 37 of 46 (80%) individuals; the location of SRF accumulation varied. Visual symptoms were mild and mainly transient, occurring in 9 participants with SRF (20%; 95% CI, 10%-33%). Only 2 participants (4%) were found to have SRF at the last study visit after discontinuation of treatment with binimetinib. Both had Snellen-measured visual acuity of 20/25 or better.

Conclusions and Relevance  The presence of SRF was common in study participants undergoing treatment with the MEK inhibitor binimetinib. Visual symptoms were mild and mainly transient. The presence of SRF did not lead to permanent ocular sequelae. Cessation of life-extending treatment with MEK inhibitors is not indicated when SRF is present.

Figures in this Article


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Figure 1.
MEK-Associated Subretinal Fluid (SRF)

Yellow-orange elevated areas subfoveally (A) and along arcades (A and D). Elevated areas are better visualized on infrared imaging (B and E), which highlights small pockets of SRF temporally (B). Subretinal fluid is seen subfoveally (C) and along temporal arcades (C and F). Green lines (B and middle line in E) represent the location of the optical coherence tomographic images (C and F).

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Figure 2.
Location of Subretinal Fluid (SRF) Accumulation

A, Pockets of subfoveal SRF are present under the interdigitation zone. B, Large pockets of SRF are seen along the arcade vessels. C, A subtle diffuse layer of SRF is present under the interdigitation zone with a localized pocket of SRF temporally. Green lines in the infrared images (left, middle line of B) represent the location of the optical coherence tomographic images (right).

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Figure 3.
Serial Optical Coherence Tomography (OCT) Before and After Receiving a Dose of Binimetinib

Serial OCT of a single study participant acquired prior to dosing (A and B) and hourly thereafter (C-F). Subtle subretinal fluid (SRF) is seen at 1 hour, reaches its peak at 3 hours, and is resolved by 4 hours after the dose.

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Figure 4.
Life Table Analysis of MEK-Associated Subretinal Fluid (SRF)

Cumulative probability of having SRF detected during a study visit over time in 2 subgroups.

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