Sir,
We read with interest Duncan et al's1 article published in the August edition of the Eye.
We have made similar observations in patient's taking R05126766 (a combined RAF and MEK inhibitor) for advanced stage cancers and found retinal changes to be common.
MEK inhibitors act upon the mitogen-activated protein kinase (MAPK) pathway, which is upregulated in a number of cancers. R05126766, the first-in-human combined RAF/MEK inhibitor, offers dual inhibition on the MAPK pathway and superior cascade blockage.2, 3 Ocular toxicities were reported in up to 50% of patients.2
Despite increased use of MEK inhibitors,3, 4 there has been limited ophthalmic literature. We would like to share our experiences regarding them.
We retrospectively analysed clinical notes for a 15-patient cohort, commenced on R05126766 monotherapy, as part of an ongoing prospective phase 1/2 trial. Each patient had baseline ophthalmic assessment and at least one follow-up while taking R05126766. The examinations were performed by the same consultant ophthalmic specialist (PU).
Retinal changes, including central serous retinopathy and pigment epithelial detachments were seen in eight patients. Six patients were symptomatic, describing blurred vision, scotomas, and two patients described a blue discolouration. We also noted that 75% of the patients who developed ocular toxicity complained of a rash, compared with only one patient (14%) without ocular toxicity. Please see Table 1 for results summary.
Table 1. Summary table showing results for the eight patients.
| Case no | Age | Sex | Type of cancer | Signs | Confirmed on OCT | Onset | Rash |
|---|---|---|---|---|---|---|---|
| 1 | 57 | M | Colorectal | Bilateral CSR | Yes | 1 Month | Yes |
| 2 | 50 | M | Adrenal | Bilateral CSR | Yes | Day 1 | Yes |
| 3 | 62 | M | Metastatic melanoma | unilateral CSR | Yes | 1 Week | Yes |
| 4 | 54 | M | Metastatic melanoma | Bilateral PED | No | 2 Months | Yes |
| 5 | 64 | M | Metastatic colorectal | Unilateral PED | No | 4 Months | No |
| 6 | 40 | F | Metastatic melanoma | Unilateral RPE changes | Yes | 1 Week | Yes |
| 7 | 58 | M | Colorectal | Unilateral PED | No | 1 Week | Yes |
| 8 | 64 | F | Metastatic melanoma | Unilateral PED | Yes | 1 month | No |
The onset of symptoms varied from 1 day to 4 months. Conclusive follow-up was not achieved because of poor patient health, with quite a number dying before resolution of their symptoms.
We have observed a high incidence of retinal pathologies in this small group of patients taking combined RAF/MEK inhibitors. We agree with the conclusions made by our colleagues Duncan et al and would recommend that baseline ophthalmic assessment with optical coherence tomography should be obtained in all patients before commencing MEK inhibitor chemotherapy.
As MEK inhibitors continue to be developed,3, 4 we predict an increased incidence of associated ocular toxicities, which may be more common than first realised. It is important, therefore, that general ophthalmologists are aware of these drugs. Further understanding of the aetiology and management of complications is needed.
The authors declare no conflict of interest.
Footnotes
This study was presented in part as a poster at The Royal College of Ophthalmologists Annual Congress 2014, Birmingham, UK.
References
- 1Duncan KE, Chang LY, Patronas M. MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. Eye 2015; 29: 1003–1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodéré F et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res 2012; 18(17): 4806–4819. [DOI] [PubMed] [Google Scholar]
- 3Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol 2014; 11(7): 385–400. [DOI] [PubMed] [Google Scholar]
- 4Wang D, Boerner SA, Winkler JD, LoRusso PM. Clinical experience of MEK inhibitors in cancer therapy. Biochim Biophys Acta 2007; 1773(8): 1248–1255. [DOI] [PubMed] [Google Scholar]