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

Across the four included studies, 655 patients received at least one dose of cobimetinib and comprised the safety-evaluable population for analysis.

Incidence and Severity

A total of 117 patients (17.9%) had at least one SR and/or RPED event, with a total of 164 events reported (Table 2). Second and third occurrences were infrequent, with 24 patients (3.7%) having two or more events, and four patients (0.6%) having three or more events. The most frequently reported events by Medical Dictionary for Regulatory Activities preferred terms were chorioretinopathy (n = 42; 6.4%), MEK inhibitor-associated SR (n = 17; 2.6%), retinal detachment (n = 15; 2.3%), retinopathy (n = 13; 2.0%), and detachment of retinal pigment epithelium (n = 15; 2.3%).

Table 2 Frequency of SR/RPED by MedDRA preferred term

The majority of SR/RPED events were grade 1 or 2. Grade 3 events were uncommon, occurring in ten patients (1.5%), and included chorioretinopathy (n = 4), retinal detachment (n = 2), retinopathy (n = 2), macular detachment (n = 1), and detachment of the retinal pigment epithelium (n = 1). There were no grade 4 or 5 events. Serious events occurred in four patients (0.6%): grade 1 retinal detachment (n = 1), grade 2 chorioretinopathy (n = 2), and grade 3 chorioretinopathy (n = 1).

Time to Onset of First SR/RPED Event

First occurrence of SR/RPED typically occurred within the first two cycles of treatment (Table 3). Median time to onset was 15 days (range 7–111) in the CO39721 study and 25–80 days (range 2–988) across the three supporting studies. In the CO39721 study, median time to onset for the second occurrence was 18.5 days (range 15–126) and median time to third occurrence was 20.5 days (range 14–27).

Table 3 Time to onset and resolution of SR/RPEDManagement and Resolution

Most SR/RPED events resolved without treatment or with a modification of dosing (Table 4). Of 117 patients with one or more occurrences of SR/RPED, 40 patients (34.1%) had a dose modification (dose reduction or interruption) of cobimetinib and nine patients (7.7%) discontinued cobimetinib. At the time of the clinical data cut-off, SR/RPED events were resolved in 67/117 patients (54.7%). More than a third of patients (45/117; 38.5%) recovered or were recovering following no change in dosing. In study CO39721, 12/25 patients (48%) recovered with no dose modification, and 4/25 patients (16%) were either recovered or recovering following dose modification.

Table 4 Dose modifications and outcomes in patients with one or more SR/RPED event

Among patients with resolution of SR/RPED, the median duration of first occurrence was 14 days (range 6–42) in the CO39721 study. Median time to resolution of the first occurrence was 26 days (range 6–591 +) in the CO39721 study and 34–97 days (range 3–2234 +) across the three supporting studies.

Risk Factors

In a univariate analysis, hypertension, autoimmune disease, pre-existing ocular confounders, male sex and age ≥50 years were identified as significant risk factors for the development of SR/RPED (Table 5).

Table 5 Risk factors for SR/RPEDOphthalmologic Assessments in Patients with SR in Study CO39721

In study CO39721, a total of 31 SR events were reported in 25 patients, with four patients having a second occurrence and two patients having a third occurrence. Serous retinopathy was bilateral in 15 patients and unilateral in five patients, for a total of 35 eyes affected.

Development of SR had no impact on best-corrected mean visual acuity. Mean visual acuity was similar at baseline (79.1 letters; n = 35 eyes), the time of first SR onset (79.1 letters; n = 35 eyes), and at the last result regardless of SR resolution (80.7 letters; n = 33 eyes).

At baseline, 23/35 eyes (65.7%) had normal indirect ophthalmoscopy results and 12/35 (34.3%) had baseline abnormalities unrelated to SR. In the 23 eyes with normal readings at baseline, indirect ophthalmoscopy results were normal in ten eyes and abnormal in 13 eyes at SR onset. Serous retinopathy resolved in 7/13 eyes; at the time of the last SR resolution, indirect ophthalmoscopy findings returned to normal in two eyes and remained abnormal in five eyes. At the last available indirect ophthalmoscopy, findings were normal in 12 eyes and abnormal in 11 eyes.

Optical coherence tomography findings of subretinal fluid were similar to those previously illustrated [15]. Thirty-four of 35 eyes (97.1%) had OCT findings related to SR, mostly as focal subretinal fluid in the fovea (22/35 eyes, 62.8%; Table S3 of the ESM). Subretinal fluid was multifocal at SR onset in 9/35 eyes (25.7%). Subretinal fluid was still present at the last available OCT in 4/35 eyes (11.4%).

At screening, 7/35 eyes (20.0%) had visual field defects (data missing for five eyes). No new visual field defects were reported during the study.

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