MEK INHIBITORS AND OCULAR ADVERSE EVENTS

Nearly a fifth of patients with cancer being treated with mitogen-activated protein kinase (MEK) inhibitors in clinical trials developed an ocular adverse event, according to a research letter published online November 17 in JAMA Oncology.

The patients were participating in several early-phase clinical trials with MEK inhibitors. Of 40 patients, 7 (18%) developed an ocular adverse effect, including bilateral central serous chorioretinopathy (CSC), retinal vein occlusion, and a severe increase in intraocular pressure.

"These cases highlight the wide spectrum of ocular adverse effects associated with the introduction of these drugs in clinical practice," say the authors, led by Robert M.J. Purbrick, MBChB(Hons), FRCOphth, from the Oxford Eye Hospital and the Oxford Experimental Cancer Centre, United Kingdom.

Several MEK inhibitors are at different stages of development and are being evaluated for several cancer types, including melanoma, as well as colon and liver cancer.

Trametinib (Mekinist, Novartis) was the first drug in this class to be approved (in 2013), for use in patients with melanoma with tumors expressing BRAF V600E or V600K gene mutations.

Last year, another MEK inhibitor, cobimetinib (Cotellic, Roche) received US Food and Drug Administration approval to be used in combination with vemurafenib (Zelboraf, Roche) for the treatment of melanoma with BRAF V600E or V600K mutations.

Study Details 

In this study, the authors reported on the ocular toxicities seen with 3 different MEK inhibitors that are at independent stages of clinical development, including ongoing studies.

They report results from 3 patient cohorts, each treated with a different MEK inhibitor.

In the first cohort, 3 of 11 patients (27%) developed bilateral CSC, multifocal in 1 patient. The 3 patients who developed CSC-like changes had no baseline abnormalities, and the changes resolved when the drug was stopped, the authors note.

In the second cohort, 2 of 19 patients (11%) developed ocular adverse effects. One patient developed a left central retinal vein occlusion and the other, a bilateral, multifocal CSC-like changes.

In the third group, 1 patient developed a bilateral, multifocal CSC-like change and a second patient experienced a severe increase in intraocular pressure.

The authors note that similar self-limiting cases of CSC have been reported in other papers, including one that reported the development of CSC in 13 of 20 patients treated with binimetinib for advanced cutaneous melanoma (Ann Oncol. 2014;25:1437-1441).

Retinal vein occlusion has also previously been reported in association with the use of MEK inhibitors, but authors also note that the "hypercoagulable state of malignancy must be considered in this patient group."

The authors also point out that paclitaxel and docetaxel, used to treat a variety of cancers, are associated with the development of cystoid macular edema.

Three patients in the current study had been treated with a taxane in addition to the MEK inhibitor, and these patients presented with retinal vein occlusion, ocular hypertension, and CSC, respectively, the authors note.

"Because the role of MEKIs [MEK inhibitors] in this patient group is yet to be fully assessed, it is important that ocular complications are monitored prospectively using appropriate validated techniques," the authors conclude.

They recommend a baseline ophthalmic examination before a new patient begins receiving treatment with a MEK inhibitor.

The Early-Phase Clinical Trials Unit receives support from Cancer Research UK. The authors have disclosed no relevant financial relationships.