Risk factors for MEK-associated retinopathy in patients with advanced melanoma treated with combination BRAF and MEK inhibitor therapy

Abstract

Background: Retinopathy is a common adverse event with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors. Little is known about the pathophysiology of MEK inhibitor-associated retinopathy (MEKAR). Since MEKAR has many similarities to central serous chorioretinopathy (CSCR), they may share common risk factors. The aim of this study was to evaluate the association between baseline characteristics and MEKAR in melanoma patients initiating MEK inhibitor treatment. Methods: Data from patients treated with cobimetinib and vemurafenib for advanced melanoma in the coBRIM trial were subjected to secondary analysis. Consistent with CSCR risk factors, assessed baseline characteristics included: age, gender, past ocular disease, weight, hypertension, diabetes, dyslipidemia, glomerular filtration rate (eGFR) and corticosteroid use. Associations between characteristics and retinopathy events (any grade and symptomatic) were evaluated using univariate logistic regression and represented as odds ratios (OR). Results: A total of 247 patients were treated with cobimetinib and vemurafenib, of whom 72 (29%) had retinopathy of any grade and 33 (13%) had symptomatic retinopathy. Patients with a history of ocular disease were at significantly higher risk of retinopathy (any grade, 44%; symptomatic, 22%) than those with no ocular disease history (any grade, 22%; symptomatic, 10%). Individuals with a history of ocular inflammation or infection were at highest risk: 4 of 5 developed symptomatic retinopathy during MEK inhibitor therapy. Increased age was associated with a higher risk of any grade retinopathy {decade increase OR [95% confidence interval (CI)] = 1.03 (1.01–1.05); p = 0.009}, while increasing eGFR was significantly associated with a decreased risk of any grade retinopathy [0.98 (0.96–0.99); p = 0.004]; the associations were not statistically significant with symptomatic retinopathy. Other assessed CSCR risk factors were not significantly associated with MEKAR. Conclusion: Age, glomerular filtration rate and history of ocular disease (particularly inflammatory eye disease) were associated with a risk of MEK inhibitor induced retinopathy. Patients who are at increased risk of MEKAR may benefit from more regular ophthalmologic assessment during treatment.