PIMASERTIB AND SEROUS RETINAL DETACHMENTS.

PURPOSE: To report a case of multifocal serous retinal detachments associated with pimasertib.
METHODS: The authors report a 26-year-old patient who developed bilateral multifocal serous retinal detachments appearing 2 days after starting pimasertib (as part of a clinical trial investigating its use in low-grade metastatic ovarian cancer) and rapidly resolving 3 days after stopping it.
CONCLUSION: The mechanism of MEK inhibitor induced visual toxicity remains unclear. The pathophysiology of multifocal serous retinal detachments as a complication of pimasertib is still poorly understood.

Case Report

This unique case demonstrates bilateral serous retinal detachments as a side effect of pimasertib. Pimasertib is an orally bioavailable MEK 1 and 2 inhibitor with potential antineoplastic activity, that is, currently used in clinical trials for ovarian cancer.

A 26-year-old woman, known to have metastatic low-grade serous ovarian cancer, started complaining of blurred vision 2 days after starting pimasertib. This was prescribed as part of a clinical trial, investigating the use of pimasertib versus placebo in the treatment of low-grade metastatic ovarian cancer. Pimasertib is given as a 60-mg tablet daily for 21 days followed by 7 days break and then the cycle is restarted. Snellen visual acuity at presentation was 20/25+2 in each eye, intraocular pressure was 14 mmHg, and the anterior segment was unremarkable. Fundoscopy showed multifocal serous retinal detachment in both eyes (Figure 1). Optical coherence tomography demonstrated striking bilateral, multifocal serous retinal detachments (Figure 2, A and B). There was no history of steroid use.

Fig. 1

Fundoscopic exam showing multi-foci serous retinal detachments.

Fig. 2

A. Optical coherence tomography of the right eye showing multifocal serous retinal detachments. B. Optical coherence tomography of the left eye showing multifocal serous retinal detachments.

Three days after emergently stopping the pimasertib due to her ocular complaint, her vision rapidly returned to normal. Snellen visual acuity had improved to 20/20 in each eye and fundoscopy revealed resolution of the serous retinal detachments (Figure 3). Optical coherence tomography showed near complete resolution of the serous retinal detachments (Figure 4, A and B). Intravenous fluorescein fundus angiography was normal after stopping the medication (Figure 5).

Fig. 3

Fundoscopic examination showing resolution of serous retinal detachments.

Fig. 4

A. Optical coherence tomography of the right eye showing complete resolution of serous retinal detachments after completing pimasertib course. B. Optical coherence tomography of the left eye showing almost complete resolution of serous retinal detachments after completing pimasertib course.

Fig. 5

Intravenous fundus fluorescein angiogram of both eyes was normal 3 days after stopping pimasertib.

Pimasertib is a MEK 1 and 2 inhibitor that modulates mitogen-activated protein kinases, which are a family of ubiquitous eukaryotic signal transduction enzymes that link extracellular stimuli to intracellular gene expression pathways allowing for various cellular responses, including adaptation and survival.1 The classic mitogen-activated protein kinase cascade, the Ras/Raf/MEK/ERK cascade, is initiated by the binding of a ligand such as a growth factor, mitogen, or cytokine to its receptor at the cell surface. This cascade is now identified as a target opportunity for the treatment of low-grade ovarian carcinoma.

Pimasertib has been used in clinical trials for the treatment of various types of cancer. Most common adverse events observed include diarrhea, rash, asthenia, anorexia, nausea, vomiting, peripheral edema, anemia, and visual disturbances including retinal vein occlusion, serous retinal detachment, and macular edema (Table 1). The underlying pathology for central serous retinopathy is reversible after drug interruption followed by dose reduction.2,3

Table 1

Current MEK Inhibitors Clinical Trials and Associated Percentages of Ocular Toxicity as Well as the Most Common Side Effects

The mechanism of MEK inhibitor induced ocular toxicity remains unclear. Many of the molecules targeted by anticancer agents are also expressed in ocular tissues, which can explain the ocular toxicity causes by such medications. There is evidence that the mitogen-activated protein kinase pathway regulates tight junctions between retinal pigment epithelial cells so that MEK inhibitors may interfere with fluid transport, resulting in the accumulation of fluid beneath the retina.4

To our knowledge, this is the first case that describes bilateral, multifocal central serous retinopathy appearing 2 days after starting pimasertib for ovarian cancer and rapidly resolving 3 days after stopping pimasertib. Multifocal serous retinal detachments have been reported with the use of other MEK 1 and 2 inhibitors.4 The pathophysiology of this complication is still poorly understood.