MEK and BRAF Inhibitors and the Risk of Ocular Toxicity

Targeted therapy is a type of anticancer treatment that interferes with specific molecules needed for carcinogenesis and tumor growth, therefore selectively targeting cancer cells as opposed to all rapidly dividing cells as is the case with traditional chemotherapy.¹ As cancer treatment advances with the introduction of new agents, ophthalmologists must be aware of the potential ocular side effects to manage patients in a manner that preserves both eye health and cancer treatment efficacy.  

MEK inhibitors (MEKi) and BRAF inhibitors (BRAFi) target the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway which regulates cellular growth, proliferation, and survival.² BRAFi were first approved for the treatment of unresectable or metastatic BRAF-mutant melanoma in 2011, and MEKi soon followed. Acquired resistance to BRAFi monotherapies led to the development of MEK and BRAF Inhibitor combination therapies, which enhance apoptosis and extend time to resistance.³ Several molecules in this class (including dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) are currently approved by the Food and Drug Administration (FDA) for the treatment of multiple unresectable or metastatic solid tumors including melanoma, non-small cell lung carcinoma, and anaplastic thyroid cancer.

The ocular adverse events (OAEs) from these drugs commonly manifest early after initiating therapy, necessitating clinical monitoring and prompt recognition by ophthalmologists. MEKi commonly cause MEKi-associated retinopathy (MEKAR) that manifests within hours to weeks after treatment initiation.⁴ BRAFi are associated with intraocular inflammation, manifesting within weeks to months of treatment.⁵ A synergistic effect in OAEs from combination therapy has been linked to earlier manifestation and increased rates of diffuse abnormalities and panuveitis compared to monotherapies.³ Management of OAEs due to these treatments depends on the inciting treatment class, as well as severity and nature of the OAEs. Management options include observation, topical, local or systemic corticosteroids, and anticancer treatment tapering or discontinuation. 

Outcomes of targeted therapy OAEs are favorable with proper management, with cases commonly regressing and having little impact on vision. In the following sections, we detail the specific OAEs for each medication class, their proposed mechanism, management options and outcomes. Understanding these aspects of OAEs can help ophthalmologists better engage with oncologists and patients, tailoring individualized approaches to cancer therapy. 

Ocular Adverse Events of MEK Inhibitors

Ocular adverse events involving the retina have been reported for all clinically tested MEKi. The incidence of OAEs in asymptomatic patients undergoing treatment with MEKi has been reported to be up to 90%.⁵ The incidence of MEKAR varies widely but has been reported in up to 70% of patients.⁵ When present, symptoms  usually occur within 1 week of treatment, and include blurred vision, metamorphopsia, photopsia, and visual disturbances. However, it is not uncommon for patients to be completely asymptomatic, therefore MEKAR can be an incidental finding. Clinically, MEKAR is characterized by self-limited serous detachments of the neurosensory retina that can be easily identified on infrared imaging and optical coherence tomography (OCT).^5,6 Subretinal fluid configurations on OCT have been termed “dome,” characterized by a dome-shaped accumulation of subretinal fluid; caterpillar, referring to a plateau, low-lying accumulation of fluid; wavy, referring to a linear collection of small dome-shaped fluid collections; and splitting, characterized by a broad, low-lying accumulation of subretinal fluid.⁶ The clinical presentation can resemble that of central serous chorioretinopathy (CSCR). However, MEKAR differs from CSCR as it is most often bilateral, and it is characterized by multifocal neurosensory retinal detachments and normal choroidal thickness.⁶ MEKAR tends to have a fluctuating course, and cases are often self-limiting and do not interfere with activities of daily living.

Retinal vein occlusion (RVO) occurs less frequently than MEKAR but has been reported during treatment with MEKi, reaching 14% in one clinical trial of combination treatment with trametinib.⁵ Other rarer OAEs for MEKi include punctate keratitis, dry eye, corneal erosion, conjunctivitis, episcleritis, anterior uveitis, epiphora, and periorbital edema. Cataracts have been reported with refametinib and cobimetinib. Some of the symptoms related to these conditions can be bothersome and impact the quality of life of patients, therefore they should be appropriately controlled. 

Subretinal fluid accumulation has been linked to the presence of aquaporin in retinal pigment epithelium (RPE) cells and MEK/ERK pathway involvement in the regulation of aquaporin density.⁷ Researchers suspect that the MAPK pathway plays a role in post-mitotic tissues, including the neurosensory retina and RPE, specifically regulating tight junctions and aquaporin 1 expression.⁸ Inhibition of this pathway would affect the outer blood-retinal barrier, therefore allowing accumulation of subretinal fluid.⁸ After RVOs precipitated the termination of a clinical trial for MEKi PD-0325901, a team of investigators observed the upregulation of genes involved in oxidative stress, blood retinal barrier breakdown, inflammatory response, and coagulation cascade in rats.^9-11 

Managing MEKi-Associated OAEs 

Management of retinal OAEs related to MEKi include observation, topical treatments, and intravitreal injections. A 2016 study recommend using the Common Terminology Criteria for Adverse Events (CTAE) and baseline visual acuity to guide management.⁷ “Grade 1 and 2” toxicities, defined as asymptomatic and symptomatic patients with visual acuities of 20/40 or better should be managed with close observation and no interruption of MEKi, as abnormalities usually regress within days of continued anticancer treatment. 

Patients with “Grade 3” toxicity, with visual acuity less than 20/40, should discontinue MEKi treatment and may be rechallenged at the same dose when symptoms resolve with close monitoring. For “Grade 4” toxicities, characterized by severe vision loss (visual acuities of 20/200 or worse), MEKi treatment should be discontinued and may be rechallenged at a lower dose when symptoms and OCT findings resolve. Researchers affiliated with the Spanish Miguel Servet University Hospital,  proposed a similar approach, with baseline evaluation of patients before and 3 monthly visits after initiation of MEKi, with exams as needed for fluid monitoring. 

Patients should be proactively informed about the possible ophthalmologic side-effects of MEKi. Discussing the transitory nature of MEKAR may help to decrease anxiety. Patients should be encouraged to monitor central vision at home with Amsler grids and instructed to seek urgent care if they experience any visual impairment that affects daily activity.

For patients who develop RVO while on MEKi, traditional treatments with intravitreal anti-vascular endothelial growth factor (VEGF) and steroid injections are recommended as needed for cystoid macular edema (CME). Treatment interruption for RVO can be considered for preventing occlusive events and systemic complications of the prothrombotic state.

Note that discontinuation of a potentially life-saving treatment with MEKi is reserved for sight-threatening ocular toxicity. This emphasizes the importance of communication between oncologists and ophthalmologists to ensure optimal outcomes of ocular toxicity during anticancer therapy. 

BRAF Inhibitor Ocular Adverse Events

The most common OAE in BRAFi monotherapy is introcular inflammation.^12,13 In a retrospective review of BRAF mutant cutaneous melanoma patients treated with vemurafenib, researchers described OAEs in 22% of patients, with the most common being uveitis (4%), followed by conjunctivitis (2.8%), and dry eyes (2%).¹² In this group, only 1 patient developed central retinal vein occlusion (CRVO) requiring treatment discontinuation. Time from the initiation of treatment to uveitis onset can range from weeks to months. 

When intraocular inflammation related to BRAFi occurs, patients report typical symptoms including blurred vision, photophobia, redness, tearing and discomfort. In a retrospective single center review comparing vemurafenib, dabrafenib, and encorafenib, researchers noted 1.6% of patients experienced OAEs.¹³ The most common side effect was uveitis, followed by dry eye and CSCR. They also found a shorter interval to OAEs and disproportionate dry eye syndrome for patients taking encorafenib compared to vemurafenib and dabrafenib.¹³ Additional reports have described more severe uveitis, such as Vogt-Koyanagi-Harada (VKH) disease, which lead to discontinuation of BRAFi therapy.^14,15 

As for combination MEK and BRAF inhibitor therapy, a 2021 pharmacovigilance study confirmed increased toxicity when used together.¹⁶ There was also a significant association between combination therapy and all types of uveitis, as well as higher rates of panuveitis. Disproportionately higher rates of VKH syndrome were present in both BRAFi monotherapy and MEK and BRAF inhibitors combination therapy compared with MEKi monotherapy.¹⁶ 

When investigating OAEs secondary to treatment with vemurafenib, a study published in the American Journal of Ophthalmology listed multiple possible mechanisms that could explain the pathogenesis of uveitis, including direct vemurafenib action on subclinical metastatic melanoma cells in the uveal tract, inflammatory response to antigens shared by melanoma and melanocytes in the choroid, direct inhibition of downstream ERK in ocular tissues, and paradoxical activation of ERK.¹² The study authors endorsed the paradoxical activation of ERK stimulating T-cell proliferation and interleukin-2 production as the most likely mechanism of uveitis from vemurafenib. 

As for the synergistic effect for ocular toxicity seen in MEK and BRAF inhibitor combination therapy, it has been proposed it may be due to increased effective signaling within the MAPK pathway from two targets. The interference of BRAFi/MEKi with the MAPK pathway, which is involved in the T-cell receptor signaling pathway, could lead to similar changes as observed in cases of panuveitis or VKH disease.¹⁷ 

BRAF Inhibitor Complication Management and Outcomes

In the aforementioned American Journal of Ophthalmology study, all 23 patients with uveitis were able to continue vemurafenib; however, the dose was reduced for 6 patients.¹² No cases of grade 4 uveitis (blindness) were observed, and most patients with uveitis were effectively treated with topical or periocular corticosteroids, cycloplegic agents, and pressure-lowering agents as needed. A subset of patients required a regimen of systemic or intraocular steroids. Only 3 cases required discontinuation of vemurafenib, including 1 case of unilateral ischemic central RVO, 1 case of diplopia, and 1 case of persistent ocular hyperemia, and conjunctivitis.¹² Authors of a 2023 study noted most OAEs were successfully treated with local ophthalmic therapy, but 2 patients discontinued BRAFi treatment due to severe panueveitis refractory to aggressive topical corticosteroids.¹³ Discontinuation of treatment has been reported for some cases of VKH-disease related to BRAFi use.^14,15

No consensus algorithms have been developed for management of uveitis due to BRAFi monotherapy. Patients should be monitored regularly and intraocular inflammation should be treated with topical, local or systemic steroids based on the severity of clinical manifestations.¹² 

One algorithm has been proposed to help guide switching or stopping BRAFi or MEKi for patients with BRAFi/MEKi OAEs.¹⁶ Notably, the decision to discontinue only 1 agent could be considered when there is a specific clinical pattern characteristically associated with one of the drugs. Local therapy can avoid unnecessary discontinuation of life-saving cancer treatment; however, ophthalmologists should be involved in multidisciplinary treatment decisions regarding BRAFi therapy with respect to vision-threatening side effects.

Ocular adverse events are associated with the use of MEK and BRAF inhibitors, and combination therapies in cancer treatment. MEKi are linked to MEKAR, characterized by multifocal serous retinopathy, and occasionally visual disturbances. BRAFi monotherapy is most commonly associated with uveitis. Combination MEKi/BRAFi therapy has been shown to exhibit additive effects, leading to earlier manifestation and higher rates of diffuse abnormalities. Although there are no clear consensus-guidelines, the management of OAEs generally involves clinical observation, steroid treatment, and anticancer treatment reduction or discontinuation. Recognizing ocular toxicity specific to each drug class can help guide preferential discontinuation of the offending medication. 

With proper management, the outcomes of these OAEs are favorable, often regressing without permanent visual impairment. Early monitoring with close communication between ophthalmologists and oncologists is crucial for an individualized approach to cancer therapy, ensuring optimal anticancer treatment and ocular health. 

Tommy Bui, BS, is a medical student at the Medical College of Georgia, Augusta University Medical Center, Augusta, GA. Basil K. Williams Jr., MD, is an associate professor of clinical ophthalmology at Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, and Maura Di Nicola, MD, is an assistant professor of clinical ophthalmology at  Bascom Palmer Eye Institute.

Disclosure: Maura Di Nicola, MD has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. No conflicting relationship exists for any author.