Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study

Abstract

Background: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600-mutated melanoma treated in the Phase III coBRIM study.

Methods: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms.

Results: Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014).

Conclusions: Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600-mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012.

Keywords: Cobimetinib; MEK inhibition; Melanoma; Serous retinopathy; Visual disturbance.

Figures

Fig. 1

Bilateral serous retinopathy (left eye shown) in a 64-year-old woman receiving cobimetinib combined with vemurafenib. At baseline, ophthalmic examination findings were normal, and no retinal abnormalities were detected either on bidimensional near-infrared image of the macula or on cross-sectional optical coherence tomography scan across the fovea (first row). On study day 8, the patient had nonserious grade 2 bilateral blurred vision. On study day 10, ocular examination with indirect ophthalmoscopy revealed bilateral serous subfoveal neurosensory detachment (i.e. subretinal fluid). Retinal imaging showed that detachments of the neurosensory retina were not limited to the fovea but were multiple and extended across the macular area (second and third rows, white arrows). A diagnosis of nonserious grade 2 serous retinopathy was made, and no treatment was administered for this event. On study day 14, the event of neurosensory detachments was considered resolved on indirect ophthalmoscopy, and blurred vision was considered resolved on study day 15. On study day 21, retinal imaging confirmed resolution of the retinal abnormalities (fourth row). The investigator considered blurred vision and serous retinopathy to be related to cobimetinib combined with vemurafenib. Treatment with cobimetinib combined with vemurafenib was permanently discontinued on study day 36 because of other adverse events, including pyrexia, rash, and elevated liver enzyme levels, with consideration of the previous event of serous retinopathy

Fig. 2

First onset and severity grade of serous retinopathy in the coBRIM study, per patient