Evaluation of immune related adverse events following extended interval dosing of immune checkpoint inhibitors.

Abstract

e14605 Background: Increased use of immune checkpoint inhibitors (ICI) has resulted in a rise in immune related adverse events (irAEs). In 2019, pembrolizumab and nivolumab received approval for extended interval (EI) dosing at 400 mg intravenous (IV) every 6 weeks and 480 mg IV every 4 weeks, respectively, compared to the standard interval (SI) dosing of 200 mg IV every 3 weeks and 240 mg IV every 2 weeks, respectively. Since EI dosing has been implemented, clinicians have hypothesized increased dosing may lead to more irAEs. Mixed results have been published to date with discordant results between studies. The aim of this study was to investigate the incidence and grade of irAEs, including multisystem adverse events (ms irAEs) in SI versus EI dosing in a real-world community-based hospital system in the United States of America. Methods: We performed an Institutional Review Board approved retrospective study of all patients 18 years or older who received SI or EI dosing of pembrolizumab or nivolumab from 2015 through 2021. An irAE was considered connected to the specific dosing group if it was observed after the first date of stated dosing and within 90 days after last dose of such dosing. Statistical analysis included descriptive statistics, Wilcoxon signed-rank test, Fisher’s exact test, and Kaplan-Meier survival analysis and was performed in R version 4.2.2 at a significance level of 0.05. Results: Our study included 458 patients who were 99% white, 59% male, and an average age of 67 years. There were 354 (77%) patients in the SI group and 104 (23%) in the EI group. The overall incidence of irAEs was 32% (146 patients), of which 37% (54 patients) presented at some point with ms irAEs. There was no significant association between dosing group and presence of irAEs (p = 0.087), grade groups 1-2 vs > 3 (p = 0.7), or ms irAEs (p = 0.13). The incidence of irAEs was 34% (120 patients) in the SI group with a distribution of grades 1-2-3-4-5 being 39-62-25-5-1, respectively. The incidence of irAEs was 25% (26 patients) in the EI group with a distribution of grades 1-2-3-4-5 being 18-27-11-1-0, respectively. In the SI group there were 41 (34%) patients with ms irAEs compared to 13 (50%) in the EI group. There was a significant association between dosing groups and overall survival (p < 0.001). Conclusions: Our results lend data to suggest there is indeed no statistically significant risk of increased irAEs with EI dosing. However, there may be a clinically significant trend toward increased ms irAEs in EI dosing that needs further investigation with comparisons of comorbid conditions that increase risk of autoimmune reactions. Of note, the OS in EI dosing group was statistically significant but likely heavily confounded due to patient selection bias, this may also be an avenue for future research to be conducted with a randomized clinical trial.