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. 2017 Apr;5(4):312-318.
doi: 10.1158/2326-6066.CIR-16-0237. Epub 2017 Feb 28.

Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients

Guillermo De Velasco  1   2 , Youjin Je  3 , Dominick Bossé  1 , Mark M Awad  1 , Patrick A Ott  1 , Raphael B Moreira  1 , Fabio Schutz  4 , Joaquim Bellmunt  1 , Guru P Sonpavde  5 , F Stephen Hodi  1 , Toni K Choueiri  6
Affiliations

Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients

Guillermo De Velasco et al. Cancer Immunol Res. 2017 Apr.

Erratum in

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.

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Conflict of interest statement

Conflict of Interest

GdV: Consulting or Advisory Role Pfizer, Bayer, Janssen, Novartis. MMA: Consulting or Advisory Role - Abbvie; AstraZeneca/MedImmune; Boehringer Ingelheim; Clovis Oncology; Genentech; Merck; Pfizer. JB: Consulting or Advisory Role - Astellas Pharma; Genentech; Merck; Novartis; Pfizer; Pierre Fabre. GPS: Consulting or Advisory Role - Agensys; Argos Therapeutics; Bayer; Genentech; Merck; Novartis; Pfizer; Sanofi. FSH: Consulting or Advisory Role - Amgen; Genentech/Roche; Merck Sharp & Dohme; Novartis TKC Consulting or Advisory Role - Bayer; Bristol-Myers Squibb; Eisai; Foundation Medicine; GlaxoSmithKline; Merck; Novartis; Paometheus; Pfizer; Roche/Genentech. JY, RBM, PAO, FS: No Relationships to Disclose

Figures

Figure 1
Figure 1
Flow diagram of the systematic review
See this image and copyright information in PMC

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