title: Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: De Velasco
authors.affiliation: Department of Food and Nutrition, College of Human Ecology, Kyung Hee University, Seoul, Korea.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Je
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dominick
authors.initials: D
authors.lastname: Bossé
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Raphael B
authors.initials: RB
authors.lastname: Moreira
authors.affiliation: Department of Medical Oncology, Hospital São José, Beneficência Portuguesa de São Paulo, Brazil.
authors.forename: Fabio
authors.initials: F
authors.lastname: Schutz
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Division of Oncology and Hematology, University of Alabama, Birmingham, Alabama.
authors.forename: Guru P
authors.initials: GP
authors.lastname: Sonpavde
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. toni_choueiri@dfci.harvard.edu.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri