Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective

Abstract

Background: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ.

Methods: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes.

Findings: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951).

Interpretation: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research.

Funding: Paul Gougis was supported by the academic program: "Contrats ED: Programme blanc Institut Curie PSL" for the conduct of his PhD. Baptiste Abbar was supported by "the Fondation ARC Pour le Rechercher Sur le Cancer". The RT2L research group (Institut Curie) was supported by the academic program "SHS INCa", Sanofi iTech award, and by Monoprix∗.

Keywords: Cancer; Fatal; Immune checkpoint inhibitors; Immune-related adverse events; Myotoxicity; Pharmacology; Pharmacovigilance.

Fig. 1

Study flow-chart.

Fig. 2

Evolution of the reporting. Evolution of the reporting of ICI (immune checkpoint inhibitor) and their combinations (A), of cancer indications (B), and fatality rate (C) in the 50,347 cases associated with an immune related adverse event (irAE, narrow definition) in VigiBase since 2008 until 2023, by period of time. In D is shown the evolution of the different types of reported irAE (n = 60,323 narrow irAE) within 50,347 cases. p-values were computed by χ²-trend. Anti-PD1+anti-PDL1 represented 0.1% of ICI types and is not shown.

Fig. 3

Counts of immune-related adverse events (irAE) reported in VigiBase by organ system (A) and time to onset (TTO) per specific irAE (B). Overall number of irAE per organ system (narrow definitions, n = 50,347 cases and n = 60,323 distinct irAE). Details of the different specific irAE within each organ system is available in Supplementary Fig. S4. TTO were calculated using the delay between ICI start and irAE onset. “n” is the number of irAE with TTO available (N_total = 21,305). Boxplots represents the median, [interquartile, IQR, edge of the box] and 1.5 x IQR (moustache) for the TTO of each irAE. The percentage of patients having developed the specific irAE is indicated at the level of the dotted line at 1 month, 3 months, 1 year, and 1.5 years for each irAE.

Fig. 4

Heatmap of risk factors associated with the reporting of the 25 specific irAE (immune-related adverse events). Each irAE (narrow definitions) was compared with the control population including overall cases without those carrying a term associated with a broad or narrow definition of the studied irAE. The OR (odds-ratio, only shown if significant; empty squares for reference) were computed by multivariate logistic regression. For cancer and country types, the reference group was cases without the studied cancer or country type. Detailed analysis per irAE is available in Supplementary Fig. S6.

Fig. 5

Overall fatality, resolution and recurrence rates after rechallenge per specific immune-related adverse event (irAE). Overall fatality (red), resolution rate (non-resolved in yellow, ICI being withdrawn or pursued in the subset of non-fatal cases), and recurrence rate (orange) after ICI rechallenge (in cases with a first irAE previously resolved after ICI withdrawal) for the 25 specific irAE. Resolution of an irAE can also correspond to adequate medical intervention resolving the condition (such as substitution of an endocrine defect), and not necessarily reversion ad-integrum to the physiological status prior to ICI start. N_ev is the total number of cases in which the data was evaluable. Data with less than 10 cases as N_ev are grayed out.

Fig. 6

Factors associated with overall fatality. Univariate (circles) and multivariate (squares) analysis (OR (^95%CI), odds-ratio and its 95% confidence interval) of factors associated with overall fatality (n = 5709) in cases with immune-related adverse events (irAE, n = 50,347 narrow).