The programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are a class of checkpoint inhibitors approved to treat a variety of malignancies, including melanoma, Hodgkin lymphoma, non-small-cell lung carcinoma and other advanced-stage cancers.1 The first PD-1/PD-L1 drugs to be approved were pembrolizumab and nivolumab in 2014 for melanoma, followed by atezolizumab in 2015 for non-squamous small cell lung cancer, and durvalumab in 2017 for urothelial carcinoma.2 Since then, the number of clinical trials investigating these drugs have increased dramatically. An April 16 2020, search of clinicaltrials.gov reveals 3097 clinical trials testing the PD-1/PD-L1 inhibitors nivolumab, pembrolizumab, atezolizumab and durvalumab.

The PD-1/PD-L1 inhibitors are known to cause unique immune-related adverse effects in almost every organ system due to their non-specific immune activation. Common immune-related adverse effects include pneumonitis, colitis and hepatitis.1 3 Endocrinopathies such as type 1 diabetes mellitus and neurotoxicity have also been reported.3 PD-1/PD-L1 inhibitor-associated adverse events (AEs) in the eye are also known to occur, but are rare and therefore less well-studied. Case reports, case series, safety analyses, and some observational studies have shown that these drugs can cause inflammatory eye disease, such as uveitis,3–9 scleritis,8 dry eye syndrome,4 5 9 10 optic neuropathy9 and orbital myopathy.11 Additionally, ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitor in a similar class as PD-1/PD-L1 inhibitors, has been documented to cause potentially blinding conditions such as optic neuropathy,12 13 orbital inflammation,14 15 ophthalmopathy,16 and orbital apex syndrome.17 Though uveitis is a potentially blinding condition, only a few large-scale studies focusing on ocular AEs have been performed to date.7 11 18 19 So far, these studies have shown that inflammatory eye disease AEs tend to be rare, ranging from a prevalence of <1% of uveitis in drug manufacturers prescribing information20–24 to 3.6% in a large retrospective review of a large ophthalmology electronic health record registry.19

In lieu of large prospective observational studies, retrospective analyses of large ocular AE databases can be performed, such as the recent analysis of the Food and Drug Administration’s Adverse Events Reporting System Database (FAERS) conducted by Fang et al.18 or the analysis of the American Academy of Ophthalmology Intelligent Research in Sight Registry (IRIS).19 The FAERS database has a large sample size, but is limited by its lack of clinical and demographic information, while the IRIS registry has detailed ophthalmologic notes but less information on non-ocular conditions. In this study, we analyze two databases of AEs from the US National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP), the largest public sponsor of oncology clinical trials globally. This study, therefore, aims to analyze ocular AEs associated with PD-1/PD-L1 inhibitors submitted to the two separate and overlapping CTEP databases.

At the time of database queries, CTEP had opened 116 clinical trials using at least 1 PD-1/PD-L1 inhibitor as study drugs, either as monotherapy or in combination with other agents. From these 116 trials, 7727 patients were enrolled in interventional arms with at least one PD-1/PD-L1 inhibitor. Demographic information for the 7727 patients exposed to the PD-1/PD-L1 inhibitors is presented in table 1. A total of 272 unique ocular AEs from 213 patients were found in the routine AE database and a total of 59 unique SAEs from 47 patients were found in the SAE database (table 1, figure 1). The prevalence of all persons with reported ocular AEs is potentially as low as 259/7727 persons (3.3%).

An adjustment to the denominator of patients within the CDUS database is necessary for assessment of the prevalance of ocular AEs of any grade. As the denominator of 7727 does not generally include AEs from phase III trials, (unless those AEs were expeditiously reported to CTEP-AERS) the 3.3% prevalence likely underreports the true prevalance. Excluding trials that do not report routine AEs to the CDUS database results in a total patient population of 3255 patients on treatment arms involving the study drugs of interest. Since the number of patients who had ocular AEs on this subset of trials is 242 patients, the estimate of the prevalence of ocular AEs could be as high as 242/3255 (7.4%).

Within the routine AE database, the most common study drug associated with ocular AEs was nivolumab, reflecting the higher number of trials sponsored by CTEP using this agent. In the routine ocular AE group, 103 patients (48%) were exposed to both nivolumab and ipilimumab, a CTLA-4 inhibitor. Sixty-three patients (30%) were exposed to nivolumab alone. Twenty-seven patients (13%) were on pembrolizumab, 20 (9%) were on atezolizumab and 0 patients were on durvalumab. The median CTCAE grade was 1 (IQR 1–2).

In the serious ocular AE group, 10/47 patients (21%) were on nivolumab and 15/47 patients (32%) were on both nivolumab and ipilimumab. Fourteen patients (30%) were on pembrolizumab, six (13%) were on atezolizumab and two (4%) were on durvalumab. The median CTCAE toxicity grade for the events in the SAE database was 2 (moderate) (IQR 2–3).

For patients in the routine AE database, the median age at time of study enrollment was 58 (IQR 40–69). 107 (50%) patients were female and 175 (82%) were white (table 1). For the 47 patients in the SAE database, the median age at the time of ocular AE onset was 59 years (IQR 40–66). Of these 47 patients, 24 (51%) were female and 36 were white (77%) (table 1). Most patients in the SAE database had metastatic disease (32/47, 68%) and patients had a wide variety of malignancies (table 1). The most common malignancy was melanoma (eight patients), followed by invasive breast carcinoma (five patients). Ocular AEs occurred fairly early during PD-1/PD-L1 inhibitor treatment. In the routine AE database, the ocular AE occurred a median of 6 weeks (IQR 0–16) after starting the study treatment, and in the SAE database, the ocular AE occurred a median of 11 weeks (IQR 6–21) after study drug initiation (table 1).

This retrospective review of two AE databases is one of the largest analyses of serious ocular AEs due to PD-1 and PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab and durvalumab) in the USA to date. Our study found a total of 27 AEs that were potentially vision-threatening inflammatory eye conditions (13 uveitis, 1 sclerouveitis, 3 episcleritis, 1 scleritis, 1 neuroretinitis, 1 iritis, 5 keratitis, 1 optic neuritis, 1 eye inflammation) from both databases.

The prevalence of uveitis in our cohort is 14/7727 patients (0.2%), which is higher than the estimated uveitis prevalence in general US populations (57–115 cases/100,000 persons, 0.05%–0.1%).26–28 However, we acknowledge that ocular AEs may have been underreported in our cohort, as Bitton et al11 report a 0.4% prevalence of uveitis in anti-PD-1/PD-L1 immunotherapy. Though not directly comparable to an analysis of reported AEs, Sun et al19 report that 3.6% of patients seen in ophthalmology offices on checkpoint inhibitors (both anti-CTLA-4 and anti-PD-1/PD-L1) experience immune-related eye AEs. However, our results are still consistent with drug manufacturers’ prescribing information for the PD-1/PD-L1 inhibitors, which report a less than 1% incidence of uveitis or <10% of iridocyclitis.20–24

One ocular AE that likely was underreported in our cohort was dry eye. We found 50 cases of dry eye (0.6% prevalence), though literature suggests the prevalence of dry eye in PD-1/PD-L1 inhibitors ranges from 1% to 24%.4 18 29 Dry eye is usually a CTCAE grade 1 event and participating CTEP study sites are not required to report grade 1 events if they are not felt to be related to study treatment and/or do not meet the definition of ‘serious’. Because of this, there may have been underreporting of dry eye, especially if patients experienced other AEs with higher CTCAE grades.

When looking at serious ocular AEs by each PD-1/PD-L1 inhibitor in the CTEP-AERS database, we found serious ocular AEs in 2 patients on durvalumab, compared with 10 patients on nivolumab, 15 patients on nivolumab and ipilimumab, 14 patients on pembrolizumab and 6 patients on atezolizumab. However, these proportions are roughly in line with the number of patients treated with these particular agents on CTEP-sponsored trials to date.

As noted, 103 patients in the routine AE database and 15 patients in the SAE database were on combination ipilimumab and nivolumab. Ipilimumab is a CTLA-4 inhibitor that has been previously described to cause ocular AEs,3 4 7 18 30 and the combination of nivolumab and ipilimumab is known to generally increase the rate of AEs.31 As the majority of ipilimumab use is now in combination with nivolumab, it would be difficult to tease out the relative contribution of PD-1/PD-L1 inhibitors versus CTLA-4 inhibitors and thus more research is needed.

We found that when ocular AEs were reported as serious, patients frequently had to discontinue or delay their PD-1/PD-L1 inhibitors. Of the 25 patients whose serious ocular AEs were attributed to their study agent, 5/25 (20%) discontinued their study agent due to the ocular AE. Though we did not find any studies looking at treatment discontinuation due to ocular AEs, previous studies report anywhere from 4% to 39% of patients on PD-1/PD-L1 inhibitors discontinue their drugs due to any treatment-related AEs.31 32

Due to our reliance on investigator-provided clinical information, follow-up data or even ophthalmology course notes were frequently unavailable. We did not have detailed clinical information in our routine AE dataset, and even in our SAE dataset with more detailed clinical information, information was sometimes incomplete. We acknowledge that this design limited our ability to make a detailed assessment of patients’ ocular clinical histories. We attempted to rectify this situation by requesting more information for 20 patients with ocular AEs reported as serious. We ultimately received satisfactory responses from 19 study sites.

The fact that NCI uses two overlapping databases makes it somewhat challenging to calculate the prevalence of ocular AEs. As noted, we identified a total of 259 ocular AEs out of 7727 patients who were exposed to PD-1/PD-L1 inhibitors in trials of all phases. However, the CDUS database likely underreports the prevalence, as this routine AE database does not generally include adverse events from phase III trials unless those AEs were expeditiously reported to CTEP-AERS. Thus, we estimate the 3.3% prevalence likely represents the lower estimate of the true prevalence of ocular AEs. An adjustment to the CDUS database denominator was necessary to obtain the higher estimate of the true prevalence of ocular AEs. By excluding trials that do not report routine AEs to the CDUS database, we were able to find a total patient population of 3255 on treatment arms involving the study drugs of interest. Since the number of patients who had ocular adverse events on this subset of trials is 242, an estimate of the prevalence of ocular AEs could be as high as 242/3255 (7.4%). This range of 3.3% to 7.4% is the best estimate of the true prevalence available from the CDUS database, but even this range could be affected by underreporting, as the database relies on investigator-provided data.

We also acknowledge that reporting of ocular AEs varies significantly. Because the CTCAE includes several descriptions of ocular symptoms and study investigators used the CTCAE as the basis for their submission, several ocular AEs were descriptions of ocular symptoms and not formal ophthalmologic diagnoses (eg, ‘decreased vision’, ‘blurred vision’ and ‘eye pain’). Because not every patient received a formal ophthalmological examination, study sites may have only been able to report eye symptoms instead of specific diagnoses. Furthermore, variability in ocular symptom reporting could have led to delays in detection and appropriate treatment. For example, one patient had blurry vision for a week but only mentioned it during a routine study visit. Her nivolumab was held and she underwent an emergency ophthalmology consultation where it was found that she had a retinal detachment and glaucoma. Though the nivolumab was ultimately determined to be unrelated to the patient’s ocular AEs, this example illustrates how a treatment-related ocular AE could have easily been missed. In addition, we found the surprising statistic that only 64% of patients with a serious ocular AE were evaluated by ophthalmology, indicating that 36% of patients were not evaluated by ophthalmology. These points reinforce the importance of educating patients receiving immune checkpoint inhibitors about the necessity of monitoring their eyes and vision, and having study sites help patients with eye symptoms seek prompt ophthalmological evaluation.

Overall, this analysis of two large AE databases found that ocular AEs in PD-1/PD-L1 therapy are rare, can cause inflammatory ocular disease and can cause treatment delays or treatment discontinuation. Patients’ symptoms tended to improve or resolve with corticosteroid therapy. However, due to significant variability in ophthalmologic consultation, workup, treatment and reporting of these AEs, standardized clinical evaluation guidelines for ocular events and enhanced protocol guidelines on reporting of ocular AEs are needed to guide future PD-1/PD-L1 clinical trials or clinical use.