1. Copyright restrictions may apply JAMA Ophthalmology Journal Club Slides: Subretinal Fluid With MEK Inhibitor Use in Systemic Cancer Weber ML, Liang MC, Flaherty KT, Heier JS. Subretinal fluid associated with MEK inhibitor use in the treatment of systemic cancer. JAMA Ophthalmol. Published online June 16, 2016. doi:10.1001/jamaophthalmol.2016.0090.

2. Copyright restrictions may apply Introduction Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors have become more common in the treatment of systemic cancer. As use has increased, a notable adverse effect is the presence of a central serous-like retinopathy. Although symptoms have been reported, these retinal findings are relatively benign in nature and are important to recognize to avoid unnecessary 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.

3. Copyright restrictions may apply Study Design: Post hoc analysis of prospectively collected data obtained between February 29, 2012, and January 8, 2014. Participants: Fifty-one study participants with locally advanced or metastatic cancer undergoing treatment with the MEK inhibitor binimetinib in 1 of 4 clinical trials. Data Analysis: All participants underwent complete ophthalmic examination by retina specialists at a private practice in Boston, Massachusetts. Visual acuity measurement, dilated fundus examination, and spectral-domain optical coherence tomography (OCT) were performed at baseline, biweekly for 2 months, then monthly for the remainder of clinical trial participation. Data analysis was performed between December 1, 2013, and June 20, 2014. Methods

4. Copyright restrictions may apply Of the 51 participants, 18 (35%) were men; the mean (SD) age was 60 (13) years. Systemic diagnoses included metastatic cutaneous melanoma, colorectal, breast, pancreatic, and lung cancer, among others. Participants were monitored for a mean of 56 days (range, 6-364 days). Of the 51 participants, 46 (90%) developed SRF. Only 9 participants (20%) experienced symptoms at any point during the trial period. Subretinal fluid appeared as elevated, yellow-orange pockets in the fovea and/or along the arcades. The fovea was affected in 37 of the 46 participants with SRF (80%). Among the 46 participants, 14 (30%) also had a thin, diffuse layer of fluid under the interdigitation zone, apparent only on OCT. Fluorescein angiography was performed in 7 participants with SRF; no hyperfluorescence was seen. Results

5. Copyright restrictions may apply Characteristics of the Study Participants and Subretinal Fluid Results

6. Copyright restrictions may apply Results Location of SRF Fluid Accumulation

7. Copyright restrictions may apply Among the 46 participants who developed SRF, 9 (20%; 95% CI, 10%-33%) reported blurry vision, central distortion, or a central halo or circle. Symptoms occurred 45 minutes to 2 hours after drug dosing and resolved within 2 to 3 hours. Imaging with OCT confirmed the presence of subfoveal fluid in all participants who were symptomatic at the first study visit. Serial OCT images in 1 study participant demonstrated this parallel relationship between timing of symptoms and presence of SRF. Results

8. Copyright restrictions may apply Results Serial OCT Before and After Receiving a Dose of Binimetinib

9. Copyright restrictions may apply In follow-up, symptoms largely resolved within 1 month after starting the study medication despite the continued presence of SRF in all but 2 participants. Twenty-one participants (41%) had no SRF at their last visit after initiating treatment. Of them, 5 (24%) were still receiving binimetinib at that visit. Twenty-five participants (48%) had SRF present at their last visit. Of them, 14 (56%) were still receiving the study medication. Five participants (10%) did not develop SRF while receiving the study medication. Results

10. Copyright restrictions may apply Subretinal fluid was found in 90% of study participants undergoing treatment with binimetinib, more than previously reported in the literature. Visual symptoms were mild and mainly transient. Visual acuity remained within 1 line of baseline vision in more than 90% of the participants. Subretinal fluid may resolve without intervention. It persisted in 5% of study participants after discontinuation of binimetinib but was not visually significant. The presence of SRF did not lead to permanent ocular sequelae and does not necessitate the cessation of potentially life-prolonging treatment with MEK inhibitors. Comment

11. Copyright restrictions may apply If you have questions, please contact the corresponding author: –Jeffrey S. Heier, MD, Ophthalmic Consultants of Boston, 50 Staniford St, Ste 600, Boston, MA 02114 (jsheier@eyeboston.com). Conflict of Interest Disclosures All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Heier is a paid consultant for Aerpio, Alcon/LPath, Allergan, Avalanche, Bayer, EyeGate, Foresight Biotherapeutics, Forsight Vision4, Genentech, Icon Therapeutics, Janssen R&D, Kala Pharmaceuticals, Kanghong, Kato Pharmaceuticals, Novartis Pharmaceuticals, Ohr Pharmaceuticals, QLT, Regeneron, RetroSense, Santen, Shire, Stealth Biotherapeutics, Thrombogenics, Vision Medicines, and Xcovery. He receives research grants from Acucela, Alcon/LPath, Allergan, Astellas, Corcept, Genentech, Kala Pharmaceuticals, Kato Pharmaceuticals, Novartis Pharmaceuticals, Ohr Pharmaceuticals, Ophthotech, QLT, Regeneron, Sanofi/Genzyme, Stealth Biotherapeutics, and Thrombogenics. He owns stock in and is on the Board of Directors for Ocular Therapeutix. Dr Flaherty has received an honorarium as a consultant for Novartis. No other disclosures were reported. Contact Information