Ocular adverse events in PD-1 and PD-L1 inhibitors

Abstract

Background: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors can cause unique immune-related adverse effects due to non-specific immunological activation. However, less is known about adverse effects of these drugs in the eye.

Methods: Two adverse event databases were retrospectively reviewed. The two databases consisted of a routine adverse event database and a serious adverse event database of expeditiously submitted reports. Patients with any malignancy who had ocular adverse events while on PD-1/PD-L1 inhibitor treatment were included. Patients received nivolumab, pembrolizumab, atezolizumab or durvalumab alone or in combination with other anticancer agents per each trial's protocol. Databases were queried up to May 19, 2020.

Results: In the routine adverse event database, 272 adverse events from 213 patients were reported and in the serious adverse event reporting database, 59 ocular adverse events from 47 patients were reported. A lower estimate of the prevalance from the routine adverse event database showed 259/7727 patients on study treatment arms reporting ocular adverse events (3.3% prevalence). Excluding trials that do not report lower grade adverse events to the routine adverse event database results in a higher end estimate of 242/3255 patients on study treatment arms reporting ocular adverse events (7.4% prevalence). Ocular events occurred early after drug initiation (routine database: median 6 weeks, IQR 0-16, serious adverse events database: median 11 weeks, IQR 6-21). The median Common Terminology Criteria for Adverse Events grade was grade 1 (mild) (IQR 1-2) and grade 2 (moderate) (IQR 2-3) for the routine database and the serious adverse events database, respectively. In-depth analysis of the serious adverse event reports revealed varying degrees of clinical workup, with 30/47 patients (64%) receiving ophthalmological evaluation and 16/47 (34%) of patients having to delay or discontinue treatment. However, 16/47 (34%) patients experienced resolution and 14/47 (30%) patients experienced at least some improvement.

Conclusions: This is one of the largest analyses of ocular adverse events in patients treated with PD-1/PD-L1 inhibitors in the USA. We found ocular adverse events are rare complications of PD-1/PD-L1 inhibitor therapy, can be severe enough to cause treatment discontinuation/delay, and may not always be appropriately evaluated by eye specialists. Standardized plans for ophthalmology evaluation and management of ocular toxicities are needed in studies of patients treated with PD-1/PD-L1 inhibitors.

Keywords: combination; drug therapy; immunotherapy; inflammation.

Figure 1

Depiction of CTEP adverse event databases and workflow. *One ocular AE occurred before PD1/PDL1 exposure, one ocular AE occurred over 3 years after last PD1/PDL1 exposure.; CTEP-AERS, Cancer Therapy Evaluation-Program Adverse Events Reporting system; CDUS, Clinical Data Update System; FDA, Food and Drug Administration; PD-1 Programmed Death 1; PD-L1, Programmed-Death Ligand 1.

Figure 2

Graphical representation of all patients with serious ocular AEs. *Denotes patients with ocular AEs affecting the external eye (patient 9 periorbital swelling, patient 15 paralytic lagophthalmos of left eye, patient 31 right eye swelling, patient 34 preseptal cellulitis). ^aPatient 8 also on dacarbazine and doxorubicin, but ocular AE unlikely to be attributed to these agents. ^bPatient 15 was on Bevacizumab and Atezolizumab but their last dose of atezolizumab was 80 days before the ocular AE. Both agents were possibly attributed to the ocular AE. ^cPatient 19 was also on brentuximab vedotin. The ocular AE was probably attributed to Nivolumab or Ipilimumab, and possibly attributed to brentuximab vedotin. ^dPatient 22’s ocular AE also possibly attributed to Cabozantinib. ^ePatient 25’s ocular AE also possibly attributed to Etoposide, Carboplatin, and underlying small cell lung cancer. ^fPatient 35 also on Carboplatin and Etoposide, unrelated to ocular AE. ^gPatient 37 also on Cabozantinib, unrelated to ocular AE. ^hPatient 41 also on entinostat, entinostat unlikely to be attributed to ocular AE. ⁱPatient 45 also on talimogene laherparepvec, unrelated to ocular AE. AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events.