Ophthalmic Immune-Related Adverse Events and Association with Survival: Results From a Real-World Database

Abstract

Purpose: Assessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival.

Design: A retrospective cohort study.

Methods: Data were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis.

Results: A cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2 ± 11.9 years was included. The 5 most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < .0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; P = .0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < .0001).

Conclusions: Ophthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.

Figure 1.

Flow Diagram of Patient Selection from the TriNetX Database. irAE, immune-related adverse event; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4. PD-1: Nivolumab, Pembrolizumab, or Cemiplimab; PD-L1: Atezolizumab, Avelumab, or Durvalumab; CTLA-4: Ipilimumab; Combination: Nivolumab and Ipilimumab

Figure 2.

Diagram of Landmark Analysis. A 12-month landmark analysis was performed to measure the association of ophthalmic irAEs with overall survival. The index event was defined as the first day of ICI therapy. Any subjects who developed the outcome of interest (mortality) prior to the landmark time were excluded. Mortality was measured within 24 months following the landmark time. irAE, immune-related adverse event; ICI, immune checkpoint inhibitor.

Figure 3.

Overall survival according to presence of ophthalmic irAE. Kaplan-Meier estimates of overall survival after the 12-month landmark according to the presence of ophthalmic irAE by category: (a) any ophthalmic irAE, (b) neuro-ophthalmic, (c) cornea and ocular surface, (d) orbital and ocular adnexa, and (e) uveitis. HR, Hazard ratio; CI, confidence interval; irAE, immune-related adverse event.