Hyperacute Multisystem Toxicities with Immune Checkpoint Inhibitors in the FDA Adverse Event Reporting System: The Immune-Adversome

Introduction: A plethora of pharmacovigilance studies have recently described the spectrum, kinetics and other features of immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) [1], including rare but potentially fatal irAEs such as overlap syndrome (myocarditis with myositis/myasthenia gravis) [2]. Hyperacute toxicity is a recent newly described entity, albeit incompletely characterized [3]. Objective: To describe pharmacological and clinical features of hyperacute toxicities reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) through a network-based approach (the Immune-Adversome). Methods: We collected adverse events to ICIs (including antiCTLA4/PD-1/PD-L1 agents) recorded in FAERS up to December 2021. We selected reports with available information to calculate a plausible time-to-onset. Events of interest were classified into fulminant (within 7 days) and hyper-acute cases (within 21 days, i.e., during the first infusion cycle). Cases were described in terms of demographic and clinical features: age, gender, anticancer regimen (combination vs monotherapy), therapeutic indications, seriousness (hospitalization), case fatality rate (CFR, namely the proportion of cases where death was reported as outcome), co-reported symptoms, co-reported irAEs. The Immune-Adversome was estimated considering events as nodes and co-reporting as links. Analyses were performed using the R software (v. 4.1.2). Results: Out of 11,798,098 FAERS reports, ICIs were recorded in 64,112 cases (59,022 had plausible time to onset). Hyperacute cases (18,691) represented 31.7% of total ICI reports, and were mainly reported in males (62.7%), from Asia (34.8%), by clinicians (46%). No significant differences emerged with regard to seriousness between hyperacute and other cases (onset >21 days), namely hospitalization (42.9% vs 49.8%), death (27.9% vs 23.21%) and CFR (15.6% vs 13%; 16% for fulminant cases). Monotherapy was reported in the majority of cases (88.6%), mainly pembrolizumab (5,687). Pyrexia, diarrhea, fatigue, dyspnea were the most frequently reported symptoms. Hyperacute myocarditis was reported in 34.7% of cases with specified time-to-onset (862 over 1,583 total cases), with a CFR of 46.5%. Among fulminant cases, most frequent irAEs were interstitial lung disease (624), colitis (450), hypothyroidism (369), and myocarditis (234). The Immune-Adversome identified different hyperacute multisystem irAEs, including overlap s