Immune-related adverse events (irAE) have been described with
immune checkpoint inhibitors (ICI), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4), programmed cell death 1 (PD-1), and
programmed death ligand 1 (PD-L1) inhibitors (
ipilimumab,
nivolumab, or
pembrolizumab, and
atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III
immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6,528 received an ICI (
nivolumab, 1,534;
pembrolizumab, 1,522;
atezolizumab, 751; and
ipilimumab, 2,721) and 4,926 had not. Compared with non-ICI arms, ICIs were associated with more all-grade
colitis (RR 7.66, P < 0.001),
aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020),
rash (RR 2.50; P = 0.001),
hypothyroidism (RR 6.81; P < 0.001), and
pneumonitis (RR 4.14; P = 0.012). Rates of high-grade
colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms.
Ipilimumab was associated with a higher risk of all-grade
rash (P = 0.006) and high-grade
colitis (P = 0.021) compared with PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications.
Cancer Immunol Res; 5(4); 312-8. ©2017 AACR.