Grade 4 or higher immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitor (ICI) therapy occur earlier than less severe toxicities and appear linked to certain patient- or disease-related characteristics. These findings were reported in the European Journal of Cancer.

Immune checkpoint inhibitors can stimulate the immune system, leading patients to experience irAEs. Patterns of irAEs in patients taking ICIs can be unpredictable and difficult to manage; therefore, the researchers aimed to identify risk factors associated with very severe irAEs during ICI therapy.

This prospective study conducted by researchers at the Gustave Roussy Institute in Villejuif, France, evaluated data on irAEs obtained through the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) registry. Patients included in this analysis experienced irAEs while undergoing treatment for solid or hematologic cancers with ICIs, mostly involving an antiprogrammed cell death 1 (PD-1) or antiprogrammed cell death-ligand 1 (PD-L1) agent. The researchers had a goal of determining any patient- and/or disease-related characteristics that may be linked to very severe (grade 4 or higher) irAEs during treatment with these agents.

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For this study, the researchers enrolled 1187 patients from the REISAMIC registry, of whom 32.0% (380 patients) reportedly experienced 1 or more irAEs, and 2.86% (34 patients) reportedly had very severe irAEs. Among those patients who experienced any irAEs, very severe irAEs occurred in 8.95% (34 patients), and fatal irAEs were reported in 3.95% (15 patients). PD-1 or PD-L1 inhibitor monotherapy had been given to 33 of the patients who experienced very severe irAEs.

Very severe irAEs occurred at a median time of 41 days (interquartile range [IQR], 0 to 634), compared with 91 days (IQR, 0 to 1123) for irAEs grades 1 to 3 (P =.0168). The researchers reported that predictors of very severe irAEs included a performance status of 2 or higher, an elevated neutrophil-to-lymphocyte ratio, and lung cancer.

An albumin level less than 35 g/L also appeared to be a risk factor for a fatal irAE. Among very severe irAEs, pneumonitis had the highest fatality rate (26.3%), with cardiac irAEs showing a fatality rate of 16.7%.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original study for a full list of disclosures.


Ruste V, Goldschmidt V, Laparra A, et al. The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: a prospective study of the French REISAMIC registry. Eur J Cancer. Published online October 6, 2021. doi:10.1016/j.ejca.2021.08.048