Clinical and Functional Retinal Changes Associated With BRAF/MEK Inhibitor Therapy in Patients With Malignant Melanoma

Clinical, Morphological, and Electrophysiological Characteristics of MEK Inhibitor-Associated Retinopathy in Patients Treated With Combined BRAF/MEK Inhibitor Therapy for Malignant Melanoma

Patients with malignant melanoma are increasingly treated with combined BRAF and MEK inhibitor therapy. Although this treatment has significantly improved survival outcomes, it has been associated with specific retinal changes known as MEK inhibitor-associated retinopathy (MEKAR).

This observational study aimed to evaluate structural and functional retinal changes in patients treated with BRAF/MEK inhibitors. The study focused on identifying clinical characteristics of MEKAR, assessing retinal function and morphology during therapy, and examining the course of retinal changes after completion of treatment.

Patients undergoing standard oncologic treatment with BRAF/MEK inhibitors were followed prospectively with regular ophthalmologic examinations, including visual function testing, retinal imaging, and electrophysiological assessments.

The results of this study contribute to a better understanding of retinal alterations associated with BRAF/MEK inhibitor therapy and may support improved recognition, monitoring, and management of MEKAR in clinical practice.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma; Drug-Induced Retinopathy

Detailed Description

This was a prospective, observational cohort study designed to investigate clinical, morphological, and functional retinal changes in patients with histologically confirmed malignant melanoma treated with combined BRAF and MEK inhibitor therapy as part of standard oncologic care.

MEK inhibitor-associated retinopathy (MEKAR) is a recognized adverse effect of MEK inhibitor therapy and is characterized by bilateral, often multifocal serous retinal changes, predominantly involving the outer retinal layers. Although MEKAR is frequently considered reversible, its functional impact and long-term retinal sequelae remain incompletely understood.

The primary objective of this study was to assess the impact of BRAF/MEK inhibitor therapy on retinal structure and function. Secondary objectives included characterization of the clinical course of MEKAR, comparison of MEKAR incidence between different BRAF/MEK inhibitor combinations, and evaluation of persistent retinal changes following completion of therapy.

Adult patients receiving adjuvant or systemic treatment with combined BRAF/MEK inhibitors were enrolled and followed prospectively. Ophthalmologic assessments were performed at baseline, during therapy, and after completion of treatment. Examinations included best-corrected visual acuity testing, contrast sensitivity assessment, microperimetry, multimodal retinal imaging (optical coherence tomography, infrared imaging, and fundus autofluorescence), and electrophysiological testing (electrooculography and multifocal electroretinography, when indicated).

The diagnosis of MEKAR was based on characteristic retinal findings on optical coherence tomography in the absence of alternative ocular or systemic causes. Functional and morphological findings were analyzed longitudinally to assess changes over time and recovery patterns following treatment cessation.

This study was conducted in accordance with ethical standards and was approved by the competent national medical ethics committee. All participants provided informed consent prior to inclusion.

By systematically evaluating retinal structure and function in patients treated with BRAF/MEK inhibitors, this study provides clinically relevant data on MEKAR and supports improved ophthalmologic monitoring of patients receiving targeted melanoma therapy.

• Study Type: Observational
• Enrollment (Actual): 14

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Institute of Oncology Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population consisted of adult patients with histologically confirmed malignant melanoma receiving combined BRAF and MEK inhibitor therapy as part of routine clinical oncologic treatment. Participants were followed prospectively with standardized ophthalmologic examinations to assess structural and functional retinal changes associated with therapy.

Description

Inclusion Criteria:

• Adults aged 18 years or older.
• Histologically confirmed malignant melanoma.
• Treatment with combined BRAF and MEK inhibitor therapy as part of standard oncologic care.
• Ability to undergo ophthalmologic examinations and retinal imaging.
• Written informed consent provided prior to participation.

Exclusion Criteria:

• Pre-existing retinal disease that could interfere with assessment of retinal changes (e.g., central serous chorioretinopathy, macular degeneration).
• History of ocular conditions affecting the macula unrelated to BRAF/MEK inhibitor therapy.
• High myopia greater than -6 diopters.
• Uncontrolled glaucoma.
• Ocular or systemic conditions considered by the investigators to potentially confound study results.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
BRAF/MEK Inhibitor-Treated Melanoma Patients; Adult patients with histologically confirmed malignant melanoma treated with combined BRAF and MEK inhibitor therapy as part of standard oncologic care. Participants were followed prospectively with ophthalmologic examinations to assess structural and functional retinal changes associated with therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Retinal Structure and Function Parameters (OCT and Visual Function Tests)	Structural and functional retinal changes assessed using optical coherence tomography (OCT) and ophthalmologic functional testing. Outcomes include OCT-detected retinal abnormalities consistent with MEK inhibitor-associated retinopathy (MEKAR), best-corrected visual acuity (BCVA), contrast sensitivity, microperimetry, and electrophysiological assessments (electrooculography and multifocal electroretinography, when performed). Each assessment will be analyzed and reported separately according to its measurement scale.	Baseline (prior to initiation of BRAF/MEK inhibitor therapy), up to 24 months after treatment initiation, and up to 6 months after treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of MEK Inhibitor-Associated Retinopathy (MEKAR) During BRAF/MEK Inhibitor Therapy	Proportion of participants who develop MEK inhibitor-associated retinopathy (MEKAR) during treatment with combined BRAF/MEK inhibitors, based on characteristic retinal findings detected on optical coherence tomography (OCT).	From initiation of BRAF/MEK inhibitor therapy up to 24 months

Collaborators and Investigators

• Sponsor: Institute of Oncology Ljubljana

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Actual): January 31, 2025
• Study Completion (Actual): January 31, 2025

Study Registration Dates

• First Submitted: February 4, 2026
• First Submitted That Met QC Criteria: February 17, 2026
• First Posted (Actual): February 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 6, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Malignant melanoma; MEK Inhibitors; BRAF Inhibitors; MEK Inhibitor-Associated Retinopathy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma
• Other Study ID Numbers: MEKAR-BRAFMEK-ONKO-OFT-01; ERID-KSOPR-0085/2023 (Other Identifier: Clinical Research Unit, Institute of Oncology Ljubljana)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No