Ocular Adverse Events Associated with MEK Inhibitors
Silvia Méndez-Martínez, MD, Pilar Calvo, MD, PhD, Oscar Ruiz-Moreno, MD, PhD, Nieves Pardiñas Barón, MD, PhD, Jesús Leciñena Bueno, MD, María del Rocío Gil Ruiz, MD, PhD, Luis Pablo, MD, PhD
Key Words: MEK-associated retinopathy, MEK inhibitor ocular toxicity, MEK inhibitor retinopathy, MEK retinopathy, MEKAR.
Purpose
Mitogen-activated protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims to provide an update of the ocular adverse events (OAEs), especially retinal toxicity, associated with the use of MEK inhibitors.
Methods
A scientific literature search was conducted using the PubMed database up to July 2018 with the terms “MEK inhibitors” with both “review” and “clinical trials” filters. Phase I to III experimental studies and reviews were selected. Current principles and techniques for diagnosing and managing MEK inhibitor retinopathy and other ocular adverse events are discussed.
Results
In patients treated with MEK inhibitors, including asymptomatic patients, OAEs occur with an incidence of up to 90%. Mild to severe ophthalmic toxicities have been described, including visual disturbances, a two-line decrease in Snellen visual acuity, dry eye symptoms, ocular adnexal abnormalities, visual field defects, panuveitis, and retinal toxicities such as different degrees of MEK-associated retinopathy, vascular injury, and retinal vein occlusion.
Conclusion
MEK inhibitors can lead to different degrees of retinal, uveal, and adnexal ocular adverse events, causing visual disturbances or discomfort. One of the most relevant ocular adverse events of MEK therapy is MEK inhibitor–associated retinopathy (MEKAR), which is usually mild, self-limited, and may subside after continuous use of the drug for weeks or months, or discontinuation, thereby restoring the normal visual function of the retina, with some exceptions. Ocular adverse events are often associated with other systemic adverse effects that can modify the dosage of treatment, so communication with the oncologist is fundamental.
Introduction
The mitogen-activated protein kinase (MAPK) pathway is a signal transduction pathway in eukaryotic cells. MAPKs are a highly conserved family of serine/threonine protein kinases involved in numerous fundamental cellular processes including regulation of nucleosomes and gene expression, mRNA stability and translation, cell proliferation and differentiation, motility, stress response, apoptosis, and survival. These kinases play a fundamental role in oncogenesis. In general terms, a signal is transmitted through the cellular membrane to activate RAS, thereby stimulating three protein kinases—rapidly accelerated fibrosarcoma (BRAF), extracellular signal-related kinase (ERK), and MEK (MAP/ERK kinase)—which act sequentially to activate MAPK, thus modifying the activity of proteins such as transcription factors at the nuclear level to regulate transcription and modulate expression of various genes. The RAS/RAF/MEK/ERK signaling pathway is central to the pathogenesis of cutaneous melanoma and other tumors.
Most patients with cutaneous melanoma harbor oncogenes and tumor suppressor gene mutations that drive MAPK pathway activation. Mutations in BRAF are common genetic alterations and major drivers of this pathway. These mutations create a constitutively active BRAF molecule with increased kinase activity, leading to an MEK and ERK activation cascade independent of upstream RAS activation. MEK inhibitors act to suppress this cascade.
Currently, inhibiting the MAPK pathway with either BRAF or MEK inhibitors, or their combinations, is part of the treatment of BRAF-positive metastatic cutaneous melanoma and multiple solid tumors. Combined BRAF/MEK therapy enhances treatment response rates and progression-free survival and diminishes resistance development.
Nonetheless, several adverse events, including ocular toxicities, have been reported in clinical trials. Ocular manifestations are rarely described as typical anticancer therapy toxicity; however, growing awareness exists among oncologists and ophthalmologists about the need for routine ocular examinations in patients treated with MEK inhibitors and checkpoint inhibitor immunotherapy.
Because MEK inhibitors are FDA-approved for managing different types of malignant cancers, ophthalmologists must be able to recognize the clinical spectrum of ocular adverse events, grade their importance, and treat promptly to prevent irreversible blindness. This review describes ocular adverse events associated with MEK inhibitors and proposes a new algorithm for the correct management based on the Common Terminology Criteria for Adverse Events (CTCAE).
A non-exhaustive bibliographic search of the PubMed database was performed up to July 15, 2018, for Phase I to III clinical trials using the terms “MEK inhibitors” combined with “clinical trials” and “review” filters. Approximately 126 articles were identified, one-third of which were discarded due to lack of ophthalmologic focus or ocular side effect reports. Clinical trials with posted results were also searched at www.clinicaltrials.gov for additional information not fully described.
Ocular Adverse Events
Most ocular adverse events related to MEK inhibitors occur at the retina, including retinal vein occlusion and MEK-associated retinopathy (MEKAR). A broad range of OAEs involving the anterior surface, anterior segment, posterior segment, and ocular adnexal structures are described.
Defining MEKAR
The term MEKAR describes the class effect dose- and time-dependent retinal adverse events observed with MEK inhibitor use. The incidence of ocular adverse events in asymptomatic patients may be up to 90%. Clinical features include blurred vision, transient visual disturbances, flashes, and subretinal fluid, resembling central serous chorioretinopathy. Unlike central serous chorioretinopathy, MEKAR foci are usually bilateral, multifocal, relatively symmetrical, and affect the fovea. Optical coherence tomography shows fluid localized between the retinal pigment epithelium and the interdigitation zone, without gravitational dependency or inferior tracking, and typically without pigment epithelial detachment or hyperreflective dots. Changes in choroidal thickness are not consistently associated, though some suggest a thin choroid may be a predisposing factor.
Most visual acuity loss reported in clinical trials is mild (two Snellen lines), and vision usually recovers after fluid resolution. To avoid misinterpretations, the term MEKAR is used here instead of clinical trial terminology such as central serous chorioretinopathy or retinal detachment.
Historical Data on MAPK Inhibitors
BRAF mutations occur in 50%–70% of cutaneous melanomas and other tumors, representing a major driver of the RAS/RAF/MEK/ERK pathway. The first MAPK inhibitor, PD098059, was characterized in animals in 1995. Since then, many MEK inhibitors have been studied for cutaneous melanoma and other tumors.
Vemurafenib was the first selective BRAF kinase inhibitor targeting the V600E mutant and approved for cutaneous melanoma. Resistance to vemurafenib typically appeared within 5 to 7 months, often due to reactivation of the MAPK pathway by secondary mutations. Consequently, combined BRAF and MEK inhibitors were used to neutralize this paradoxical activation, overcome resistance, and prolong anticancer activity. Potent and specific inhibitors include BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (trametinib, selumetinib, cobimetinib, binimetinib), ERK inhibitors, and pan-RAF inhibitors.
First MEK Inhibitor Trials and Ocular Adverse Event Reports
CI-1040 was the first MEK1/2 selective inhibitor demonstrating clinical anticancer activity. Phase I studies showed good tolerance without ocular adverse events; however, in Phase II trials, up to 10% of patients experienced transient blurred vision and light perception alterations resolving after drug discontinuation. Periorbital edema occurred in about 12% of patients.
PD-0325901, a second-generation derivative, showed similar ocular adverse events (blurred vision, visual disturbances, periorbital edema) and some retinal vein occlusion cases that halted trials. These vascular events occurred after several months of therapy in patients with predisposing thrombosis risk factors.
Ocular Adverse Events in Clinical Trials with Trametinib
Trametinib was the first FDA-approved MEK inhibitor (2013) for metastatic cutaneous melanoma harboring BRAFV600E or BRAFV600K mutations. Clinical trials reported ocular adverse event rates up to 15% in monotherapy and 10% in combination treatments. MEKAR incidence was under 1% in various trials but included pigment epithelial detachment cases.
Studies combining trametinib with dabrafenib or other agents reported ocular adverse events ranging between 5% and 19%, including retinal vein occlusion, photophobia, increased intraocular pressure, and blurred vision.
Ocular Adverse Events in Clinical Trials with Cobimetinib
Cobimetinib was FDA-approved in 2014 for malignant cutaneous melanoma with BRAFV600 mutations, alone or combined with vemurafenib. Clinical trials showed ocular adverse event rates up to 18% in monotherapy and 11% to 27% with combined treatment. Most patients exhibited mild or no symptoms, with MEKAR and serous retinopathy appearing early in therapy. Blurred vision was reported in up to 50% of patients.
Cobimetinib has also been studied with other agents such as ipatasertib and pictilisib, with ocular adverse events reported in 5% to 19% of patients, including retinal vein occlusion.
Ocular Adverse Events in Clinical Trials with Selumetinib
Selumetinib, a MEK1 inhibitor, received orphan drug designation for differentiated thyroid cancer treatment and is heavily studied in metastatic uveal melanoma. Ocular adverse events occurred in 10% to 20% of patients in monotherapy or combination therapy. Retinal vein occlusion and MEKAR were noted in about 1% of patients.
Other MEK Inhibitors Associated with Ocular Adverse Events
Additional inhibitors such as RO5126766, RO4987655, refametinib, pimasertib, and binimetinib were associated with varying rates of ocular adverse events, including retinal vein occlusion, MEKAR, blurred vision, dry eye, cystoid macular edema, and pigment epithelial detachment.
Physiopathology of Mitogen-Activated Protein Kinase Associated Retinopathy
The MAPK pathway participates in the maintenance, protection, and repair of the retina and retinal pigment epithelium (RPE). Inhibiting this pathway may lead to ocular adverse events by affecting retinal homeostasis.
Toxicity mechanisms are posited to involve drug action on nondividing photoreceptors and RPE cells, causing retinopathy and night blindness. ERK activation in neuroretinal tissue maintains neuroretina–RPE interactions and regulates blood–retinal barrier tight junctions.
ERK also modulates ion channels controlling the outer blood-retinal barrier and aquaporin-1, a fluid transport channel in RPE cells. Thus, MEK inhibitor retinopathy likely results from combined signaling disruptions caused by MAPK pathway inhibition.
CTCAE Classification
Analyzing ocular adverse events is complicated by variability in descriptions and inconsistent use of terms like retinopathy or blurred vision, which encompass most retinal manifestations or visual symptoms.
This review proposes combining existing algorithms based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, refining visit schedules for detection and monitoring of MEKAR. The CTCAE v5.0 offers improved classification of retinal vascular disorders, MEKAR, and blurred vision compared to earlier versions.
A practical monitoring algorithm is suggested whereby asymptomatic patients undergo three monthly exams in the first three months of treatment—when MEKAR risk is highest—followed by less frequent visits as clinically indicated. Grade 1 and 2 MEKAR cases typically do not require treatment changes and are self-limited. Patients should be instructed to seek emergency care if vision impairment occurs and may use tools such as the Amsler grid for home monitoring.
Other Ocular Adverse Events Associated with MEK Inhibitors
Symptoms of anterior segment disease include punctate keratitis, conjunctivitis, epiphora, discharge, and dry eye, which can affect quality of life and require appropriate management.
Ocular inflammation described includes anterior uveitis, iritis, episcleritis, and scleritis, with symptoms such as periocular pain, photophobia, redness, and blurred vision. Uveitis, mainly anterior, can threaten sight and requires steroid treatment.
Eyelid inflammation, typically blepharitis, is characterized by hyperemic conjunctiva, desquamation, trichiasis, decreased lacrimation, and tear film dysfunction. Edemas of the eyelid and orbit are common.
Glaucoma, an intraocular pressure-related neuropathy, has been reported with some MEK inhibitors, necessitating careful intraocular pressure monitoring to prevent visual field loss.
Cataracts have been reported with certain inhibitors without a specific pathogenic mechanism proposed.
Conclusion
With the introduction of MEK inhibitors into clinical practice, various ocular toxicities have been encountered, some potentially severe such as MEK retinopathy and retinal vein occlusion. This review highlights multiple ocular adverse events and proposes a practical algorithm for MEKAR screening based on visual acuity.Early recognition of ocular adverse events and communication between ophthalmologists and oncologists are essential for optimal management.