Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies

Abstract

Introduction and Objective Serous retinopathy can be associated with MEK inhibitors, including cobimetinib. We present results of an integrated safety analysis to further characterize ocular functional and structural changes due to serous retinopathy. Methods Four studies evaluating cobimetinib at the approved dose and schedule in combination with other oncology drugs were included. Study CO39721 incorporated standardized ophthalmologic assessments to fully characterize serous retinopathy events over time and was the primary study for analysis. Supporting information was provided by studies GO28141, WO29479, and GO30182. Results In total, 655 patients received one or more doses of cobimetinib and comprised the safety-evaluable population. Overall, 117 patients (17.9%) had one or more serous retinopathy events, 24 (3.7%) had two or more events, and four (0.6%) had three or more events. Grade 3 events occurred in < 2.5% of patients. In CO39721, the median time to onset was 15 days (range 7–111); median time to resolution of first occurrence was 26 days (range 6–591 + days). Twelve of 25 patients (48.0%) recovered without a dose modification and 4/25 (16.0%) were recovered/recovering following a dose modification. The most frequent presentation of serous retinopathy was focal subretinal fluid on optical coherence tomography (62.8% of cases); in some instances (25.7% of cases), subretinal fluid was multifocal. There was no loss of visual function or visual acuity at serous retinopathy onset or resolution. Conclusions Results from this integrated safety analysis indicate that cobimetinib-associated serous retinopathy can be managed with or without a dose modification of cobimetinib at the discretion of the treating physician. No visual loss or permanent retinal damage was identified on comprehensive ophthalmologic assessments. Clinical Trial Registration ClinicalTrials.gov identifiers: NCT03178851, NCT01689519, NCT02322814, and NCT02788279. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-022-01248-2.

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

“…Other reported features of MEKAR include the thickening of the ellipsoid zone and a "starry sky" pattern of distribution of subretinal granular deposits, with suspected photoreceptor/ RPE toxicity and dysfunction [221]. These effects seem to be function-specific to the MEK inhibition itself and not compound side-effects from alternative actions, as the same clinical observations with the same levels of MEKAR severity have been also observed in patients receiving pimasertib [222] or cobimetinib (a MEK inhibitor), which was manageable in the latter case even without a dose modification, and with no visual loss or permanent retinal damage being detected [223].…”