[Ocular toxicity of targeted therapies with MEK inhibitors and BRAF inhibitors in the treatment of metastatic cutaneous melanoma]

Abstract

Introduction: Cutaneous melanoma is a malignant tumor, which develops from dermal melanocytes. Targeted therapies have changed the therapeutic management of metastatic melanoma and improved the survival rate. Among the various targeted therapies, MEK inhibitors and BRAF inhibitors have demonstrated efficacy, but they may lead to ocular toxicity. The goal of this study was to assess the incidence of ocular complications caused by the use of MEK inhibitors and BRAF inhibitors and to report their clinical features and therapeutic management.

Material and methods: This retrospective, observational, descriptive, single center study was conducted between May 2015 and December 2019 and included all patients with metastatic cutaneous melanomas treated with MEK inhibitors and BRAF inhibitors in whom ophthalmic toxicity was suspected. The data collected were demographic data (age, sex), the type of MEK inhibitors and BRAF inhibitors used, the length of time from melanoma diagnosis, mean duration of ophthalmological follow-up, time differential between starting therapy and the emergence of ocular complications, initial and final logMAR visual acuity, biomicroscopic examination of the anterior segment, dilatated fundus examination, and treatment administered.

Results: Fifty-four eyes of 27 patients with a mean age of 61.3±14.3 were included. The mean time delay between melanoma diagnosis and initiation of treatment was 23.2±8 months. Twenty patients (74%) were treated with a combination of MEK inhibitors and BRAF inhibitors (trametinib/dabrafenib), 5 patients (19%) were treated with MEK inhibitor monotherapy (cobimetinib), and 2 patients (7%) were treated with BRAF inhibitor monotherapy (vemurafenib). The mean duration of ophthalmological follow-up was 77.8±29 days, and the delay between the start of therapy and the emergence of symptoms was 87.2±78 days. The mean initial visual acuity was 0.075±0.13 logMAR, and the final visual acuity was 0.01±0.03 logMAR. Twelve patients (44%) developed ocular complications due to the targeted therapy. In the patients who received combination trametinib/dabrafenib, 5 patients (18.5%) developed clinical signs of uveitis, from acute anterior uveietis to panuveitis, and 2 patients (7.4%) developed bilateral central serous chorioretinopathy; in the patients who received cobimetinib, 4 patients (14.8%) developed bilateral central serous chorioretinopathy; and one patient (3.7%) who received vemurafenib developed acute anterior uveitis. For these 12 patients with ophthalmic side effects, temporary discontinuation of therapy was chosen for six patients (22.2%), three patients (11.1%) received half the initial dose, and for three patients (11.1%), normal dosing was continued.

Conclusion: The two main side effects of targeted therapies are uveitis for BRAF inhibitors and central serous chorioretinopathy for MEK inhibitors. A multidisciplinary approach including ophthalmologists, dermatologists and oncologists is essential in order to adapt treatment in the advent of these ocular complications.

Keywords: Anti-BRAF; Anti-MEK; BRAF Inhibitors; MEK Inhibitors; Melanoma; Mélanome; Retinopathy; Rétinopathie; Uveitis; Uvéite.