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FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial

Nti, Akosua A., MD*; Serrano, Leona W., BS*; Sandhu, Harpal S., MD*; Uyhazi, Katherine E., MD, PhD*; Edelstein, Ilaina D., BA*; Zhou, Elaine J., MD*; Bowman, Scott, MD*; Song, Delu, MD, PhD*; Gangadhar, Tara C., MD; Schuchter, Lynn M., MD; Mitnick, Sheryl, MPH, RN; Huang, Alexander, MD; Nichols, Charles W., MD*; Amaravadi, Ravi K., MD; Kim, Benjamin J., MD*; Aleman, Tomas S., MD*,‡

doi: 10.1097/IAE.0000000000002027
Original Study: PDF Only

Purpose: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma.

Methods: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31–68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment.

Results: There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged.

Conclusion: BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.

BRAF-inhibition (BRAFi) + MEK-inhibition (MEKi) + hydroxychloroquine (HCQ) caused frequent subclinical separation of the photoreceptor outer segments from the apical retinal pigment epithelium that contrasts with overt central serous detachments reported with single-agent MEKi. The abnormalities are consistent with transient interference with retinal pigment epithelium function resulting from effective BRAF + MEK inhibition.

*Department of Ophthalmology, Scheie Eye Institute at the Perelman Center for Advanced Medicine, the

Department of Medicine, Abramson Cancer Center, and the

Department of Ophthalmology Center for Advanced Retinal and Ocular Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Reprint requests: Tomas S. Aleman, MD, Perelman Center for Advanced Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104; e-mail: aleman@mail.med.upenn.edu

Supported by grants from the National Institutes of Health (NEI-K12EY015398-10), Hope for Vision, The Foundation Fighting Blindness, Macula Vision Research Foundation, The Paul and Evanina Bell Mackall Foundation Trust, The Pennsylvania Lions Sight Conservation and Research Foundation, and Research to Prevent Blindness.

None of the authors has any conflicting interests to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.retinajournal.com).

ClinicalTrials.gov Identifier: NCT02257424.

© 2018 by Ophthalmic Communications Society, Inc.