Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis

Abstract

Objectives: This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. Methods: A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I² statistics. Results: Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p < 0.0001; I² = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p < 0.0001; I² = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p < 0.0001; I² = 0%), and blurred vision (OR 2.30; 95% CI 1.50-3.54; p < 0.0001; I² = 60.1%), but not for uveitis (OR 0.99; 95% CI 0.14-7.03; p = 0.991; I² = 2.9%) or eye haemorrhage (OR 0.72; 95% CI 0.04-12.39; p = 0.824; I² = 29.8%). Conclusions: Treatment with MEK inhibitors seems to increase the risk of ophthalmic adverse effects. A need for monitoring the safety of this class of drugs exists. Regulators, clinicians, and other health care professionals must, together, be involved in this process.

A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations

“…More recently, combination strategies linking inhibition of BRAF, ERK, and EGFR have demonstrated some clinical benefits and have been shown to overcome RAF inhibitor induced paradoxical activation of MAP kinases (11,12). In these trials as well, targeting signal components, in particular, multiple components, despite promising antitumor effects, contend with inevitable toxicities in normal tissues (13). Thus, a theoretically desirable treatment strategy to overcome the obstacles may involve manipulation of factor(s) distinct from the signal components but that positively modulate the MAP kinase cascade via bystander effects and are selectively expressed or closely associated with the oncogenic features of these cancers.…”

Ocular changes in metastatic melanoma patients treated with MEK inhibitor cobimetinib and BRAF inhibitor vemurafenib

“…They did not report any statistically significant increase in the risk for uveitis or eye hemorrhage. 12 …”

“…Some groups and authors have defined MEKAR as “chorioretinopathy”, “retinal pigment epitelium detachement (PED)” or “central serous retinopathy-like”. 12 , 13 , 14 , 15 …”

A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases

“…Distinct MEK1/2 inhibitors are reported to cause atypical dose-limiting side effects, including visual disturbances [49–51], and general inhibition of ERK activity may have similar dose-limiting toxicities. As proposed here, several groups have been exploring means by which to inhibit only a subset of ERK substrates, potentially maintaining efficacy against tumors while sparing those substrates required for normal physiology.…”