Mitogen-Activated Pathway Kinase Inhibitor-Associated Retinopathy: Do Features Differ with Upstream versus Downstream Inhibition?

Introduction: Many cancers have derangement of the mitogen-activated pathway kinase (MAPK), making this pathway blockade a therapeutic target. However, inhibitors of MAPK can result in adverse effects including retinopathy. This study compares clinical and morphological characteristics of serous retinal disturbances in patients taking agents with variable inhibition of MAPK: either direct interference of mitogen-activated protein kinase kinase (MEK) or extracellular signal-regulated kinase (ERK) inhibitors or with indirect inhibition via interference with FGFR signaling.

Methods: This retrospective observational study of prospectively collected pooled data is from a single tertiary oncology referral center. Of 339 patients receiving MAPK inhibitors (171, 107, and 61 on FGFR, MEK, and ERK inhibitors, respectively) for treatment of metastatic cancer, this study included 128 eyes of 65 patients with evidence of retinopathy confirmed by optical coherence tomography (OCT). The main outcome was characteristics of treatment-emergent choroid/retinal OCT abnormalities as compared to baseline OCT.

Results: In all patients on one of three drug classes (FGFRi, MEKi, ERKi), the retinopathy manifested as subretinal fluid foci that were bilateral, fovea involving, and reversible without intervention. There were notable differences between the three classes of drugs: the proportion of patients with retinopathy, number of fluid foci per eye, proportion of eyes with intraretinal edema, and the proportion of symptomatic patients was least for the upstream target (FGFR inhibitors) and greatest for the downstream targets (MEK or ERK inhibitors).

Conclusion: This study shows MAPK pathway inhibitors may cause subretinal fluid foci with unique clinical and morphological characteristics depending on the target (FGFR, MEK, or ERK) implicated. Retinopathy is more common, more symptomatic, and more severe (more fluid foci, more expansive fluid configurations) the further downstream the MAPK pathway is inhibited.