Safety of immune checkpoint inhibitors: A systematic review of disproportionality analysis studies

Immunotherapy has fundamentally changed the treatment landscape for both solid and hematologic malignancies over the past decade. However, an evolving body of literature has reported immune-related adverse events (irAEs) involving several organs in patients treated with immune checkpoint inhibitors (ICIs). Our study aimed to systematically review published disproportionality analyses on ICIs, to summarize the current state of methodology and potential strengths of the analysis, while highlighting safety signals generated for these pharmacological groups.

A PubMed, Scopus, and Google Scholar search was conducted on November 7, 2024, and identified published disproportionality analyses of ICIs. Studies were included if they: 1) employed disproportionality analysis in pharmacovigilance databases; 2) investigations focused exclusively on ICIs; 3) analyses examining ICI-related adverse drug reactions (ADRs) (hypothesis-generating analyses and hypothesis-testing analyses); 4) mixed-methods studies incorporating disproportionality analysis with systematic reviews and meta-analysis. Data on results were categorized by ADR type and further analyzed based on exposure and comparator. We collected data on author name, database used, number of reports, age, gender, case/non-case status, exposure/comparison groups, disproportionality measures, signal definitions, confounder control, and sensitivity/subgroup analyses. We then retrospectively applied the READUS-PV (The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance) checklist to all included studies to assess their reproducibility, transparency, and quality. Additionally, we evaluated study quality based on the demographic parameters reported.

We have identified 2939 published disproportionality analysis studies. Our study included 89 eligible analyses published between 2019 and 2024. Of these, 35 specifically focused on a single irAE. More than 50% studies predominantly employed the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) as signal detection standards. The analysis of time to onset of ADR revealed a significant variation in the ICI-related ADRs, with some, such as myocarditis and arrhythmic events, manifesting rapidly within weeks, while others, including uveitis, hypophysitis, and certain endocrine disorders, exhibit a delayed onset. Hypophysitis/hypopituitarism is uniquely associated with combined anti-programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, while endocrine and irAEs are common across all ICI treatments. Nivolumab and Pembrolizumab are more frequently associated with Guillain-Barré syndrome, myasthenia gravis, colitis, hepatitis, arthritis, immune-related skin disorders, and endocrinopathies (diabetes mellitus, adrenal insufficiency, and hypophysitis). The included disproportionality studies identified several irAEs that were not detected in pre-marketing clinical trials, including rare life-threatening events like myocarditis, fractures, delayed endocrine irAEs, and hypophysitis. A total of 34 (38.2%) of published disproportionality studies failed to report essential elements needed to understand and reproduce the analyses and results. Additionally, 39 (43.8%) of studies relied on a single disproportionality method for detecting signals. Only 15 studies (16.8%) met our predefined criteria for comprehensive reporting by including all seven critical data elements, while 40 studies (44.9%) demonstrated major reporting deficiencies with three or more missing elements. Concerning gaps persist, as evidenced by 34 recent studies (38.2%) still scoring ≤ 2 points. Furthermore, a quality assessment using the READUS-PV checklist revealed that critical reporting items were frequently missing from these studies, such as information in the title, case-by-case assessments, and comprehensive sensitivity analyses and data availability statements.

The main organs affected due to ICIs are the skin, digestive, hepatic, lungs, rheumatologic, and endocrine. Disproportionality analysis in pharmacovigilance lacks standardised methods and interpretation, hindering reliable signal detection and requiring the development of clear guidelines, rigorous methodology, and collaborative efforts to improve patient safety. Additionally, the adoption of open-science practices, including protocol registration, should be implemented to enhance transparency and rigour.