Ocular safety profile of BRAF and MEK inhibitors: data from the World Health Organization Pharmacovigilance Database.

Abstract Purpose BRAF (BRAFi) and MEK (MEKi) inhibitors significantly improved metastatic melanoma prognosis. Ocular adverse effects (OAEs) represent an uncommon but disabling toxicity of these drugs. We aimed to characterize the ocular safety profile of BRAFi and/or MEKi and to detect possible safety signals. Methods We performed a retrospective, observational, pharmacovigilance study using VigiBase, the WHO global safety database. OAEs were classified according to the eye segments and to the inflammatory pattern based on to the Standardized of Uveitis Nomenclature. Associations between BRAFi monotherapy, MEKi monotherapy and BRAFi+MEKi combination therapy and OAE reporting were was assessed using the disproportionality analysis. Results were expressed with the Reporting Odds Ratio (ROR) and its 95% confidence interval (CI). Results From January, 2010 to October, 2019, 1,568 OAE cases were reported with BRAFi and/or MEKi. Among them 1,006 cases with sufficient data were included, corresponding to 310 (30.8%), 124 (12.3%) and 572 (56.9%) cases reported with BRAFi, MEKi or BRAFi+MEKi combination therapy, respectively. BRAFi monotherapy was significantly associated with the reporting of iris and ciliary body abnormalities [ROR 8.7 (95% CI 6.0-12.5)], diffuse abnormalities [ROR 7.1 (5.4-9.4)], anterior uveitis [ROR 8.6 (6.0-12.1)] and panuveitis [ROR 7.1 (5.4-9.4)]. MEKi monotherapy was associated with the reporting of retinal and choroid abnormalities [ROR 9.5 (7.4-12.2)], diffuse abnormalities [ROR 2.5 (1.1-6.1)] and panuveitis [ROR 2.5 (1.1-6.1)]. Combinations of BRAFi and MEKi therapies were associated with OAEs reporting from both drugs, with a possible synergistic or additive effect for diffuse abnormalities and panuveitis. Conclusion Our study characterizes ocular safety profile of BRAFi and/or MEKi. We identify possible safety signals for several OAEs, not previously reported with BRAFi and MEKi. Our data provide rationale for a personalized management of OAE in patients with BRAFi+MEKi combination therapy according to the type of ocular reaction.