The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: A prospective study of the French REISAMIC registry
Menée en France à partir des données du Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC), cette étude identifie les facteurs associés à la survenue d'événements indésirables très sévères de nature immunitaire chez des patients atteints d'un cancer traité par inhibiteurs de points de contrôle immunitaire
Background : Immune-related adverse events (irAEs) remain generally unpredictable, and severe irAEsremain challenging to detect early and manage. Very severe (grade IV–V) irAEs havenot been extensively characterised in prospective studies, and their predictive factorsremain unknown. Objective : The objective of the study was to describe and identify predictive factors of verysevere (grade IV–V) irAEs. Design : The French Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateursen Cancérologie (REISAMIC) registry has prospectively collected all clinically significant irAEsoccurring in patients treated with immune checkpoint inhibitors at Gustave RoussyInstitute since 2014. Setting : This was a single-centre prospective cohort study at the Gustave Roussy Institutecancer centre (Villejuif, France). Participants : The participants were all adult patients with a solid or haematological cancer treatedwith an anti–programmed cell death 1 (PD-1) or an anti–programmed cell death-ligand1 (PD-L1) and who presented a clinically significant irAE. Main outcomes and measures : The main outcomes included the clinical and laboratory characteristics of patientswith very severe irAEs, including tumour type, affected organs, time to irAE occurrence,blood cell count and serum biochemistry parameters. Results : Of the 1187 patients prospectively followed in REISAMIC between December 2014 andJanuary 2020, 380 (32.0%) had at least one irAE, and 34 (2.86%) presented with verysevere irAEs (grades IV–V). Among the 380 patients with an irAE, the distributionof very severe irAEs (grades IV–V) was 8.95% and death (grade V) was 3.95%. Amongthe 34 patients with very severe irAEs, 33 were treated with monotherapy of PD-1 orPD-L1 inhibitors, and one patient was treated with a combination of PD-1 and cytotoxicT-lymphocyte–associated protein 4 inhibitors. The median time to occurrence was shorterfor very severe irAEs (median [interquartile range]: 41 days [0–634] for grades IV–V;versus 91 days [0–1123] for grades I–III; p = 0.01680). On initiation of immunotherapy,the predictive factors for very severe irAEs were performance status ≥2, elevatedneutrophil/lymphocyte ratio and treatment for lung cancer. Conclusions : Very severe (grade IV–V) immunological toxicities occurred earlier than mild severetoxicities. On initiation of immunotherapy, patients with poor performance status,elevated neutrophil/lymphocyte ratio and lung cancer are identified at risk of developingthese very severe toxicities. These results could help to develop risk scores to identifypatients at risk of developing severe toxicities.