Immune-related adverse events occurring rapidly after a single dose of immune checkpoint blockade.

backgroundThe optimal dosing regimen for immune checkpoint blockade (ICB) remains a critical question in oncology. Although immune-related adverse events (irAEs) are common with ICB, the incidence and severity of irAEs following a single dose of anti-programmed death-ligand 1 (PD-(L)1) blockade have not yet been investigated.

methodsWe conducted a single-center prospective cohort study at Gustave Roussy (Villejuif, France), based on a population of patients with advanced or metastatic cancer, using data from the French Registre des Effets Indésirables Sévères des Anticorps Monoclonaux (REISAMIC) registry, a pharmacovigilance database dedicated to irAEs. Between December 2014 and December 2023, we included adults with solid or hematologic malignancies who presented with irAEs after the first infusion of anti-PD-(L)1 therapy, regardless of the treatment indication, and before the administration of the second dose of ICB. The main outcomes included the incidence and characteristics of irAEs, particularly severe (grade 3-4) and fatal (grade 5) events.

resultsOf the 3565 patients prospectively followed in REISAMIC, 70 (1.96%) experienced irAEs following a single infusion. Of these 70 patients, severe irAEs (grade 3-4) occurred in 20 patients (37.1%), and fatal irAEs (grade 5) were recorded in three cases (4.3%), indicating significant toxicity risks. The most frequently affected organ systems were the skin (14 (20%)), musculoskeletal system (11 (15.7%)), endocrine system (9 (12.9%)), and cardiovascular system (9 (12.9%)). Most irAEs developed within 20 days after treatment, with a median onset time of 14 days (IQR, 5-21). Multiorgan toxicities were observed in 10% of patients. Despite the severity, no predictive markers for fatality, multiorgan involvement, or early onset were identified, including pre-existing autoimmune conditions.

conclusionsThis study underscores the notable risk of severe and fatal irAEs following a single dose of anti-PD-(L)1 therapy in patients with advanced/metastatic cancer. The absence of predictive markers for fatality, multiorgan toxicities, or early onset highlights the need for enhanced patient monitoring during the initial treatment phase. Further research is needed to optimize dosing regimens, balancing safety and efficacy for safer clinical use of immune checkpoint blockade.