Key Takeaways & Executive Findings
- •• The overall incidence of any-grade immune-related adverse events (irAEs) is 65%, with high-grade (≥3) events occurring in 15% of patients receiving immune checkpoint inhibitors. • Combination therapy (anti-PD-1/PD-L1 plus anti-CTLA-4) significantly increases the risk of high-grade irAEs (RR 2.5) compared to monotherapy, with a higher rate of fatal events. • Dermatologic, gastrointestinal, and endocrine toxicities are the most common irAEs, requiring proactive monitoring and management strategies. • These findings highlight the need for personalized risk assessment and early intervention to mitigate the impact of irAEs on treatment outcomes.
Abstract
Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but they are associated with a spectrum of immune-related adverse events (irAEs). This systematic review and meta-analysis aimed to comprehensively characterize the incidence and risk of irAEs across different ICI regimens and cancer types. Methods: We systematically searched PubMed, Embase, and Cochrane Library from inception to December 2024. Randomized controlled trials (RCTs) and cohort studies reporting irAEs in patients receiving ICIs were included. Pooled incidence rates and relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Results: A total of 75 studies comprising 45,000 patients were analyzed. The overall incidence of any-grade irAEs was 65%, with high-grade (≥3) irAEs occurring in 15% of patients. The most common irAEs were dermatologic (30%), gastrointestinal (20%), and endocrine (15%). Combination therapy (anti-PD-1/PD-L1 plus anti-CTLA-4) significantly increased the risk of high-grade irAEs compared to monotherapy (RR 2.5, 95% CI 2.0-3.1). Fatal irAEs were rare (0.5%) but more frequent with combination therapy. Conclusion: ICIs are associated with a substantial burden of irAEs, particularly with combination regimens. Early recognition and management are crucial to optimize patient outcomes. These findings underscore the need for vigilant monitoring and patient education.
1. Introduction
Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for multiple malignancies, offering durable responses in a subset of patients. However, their unique mechanism of action—enhancing T-cell activity against tumors—can lead to a breakdown of immune tolerance, resulting in a spectrum of immune-related adverse events (irAEs) that can affect any organ system. These irAEs range from mild dermatologic reactions to severe, life-threatening conditions such as myocarditis, pneumonitis, and colitis. The clinical significance of irAEs is underscored by their potential to necessitate treatment discontinuation, impact quality of life, and in rare cases, lead to mortality.
Despite the growing use of ICIs, there remains considerable variability in the reported incidence and risk of irAEs across studies, partly due to differences in patient populations, cancer types, and treatment regimens. A comprehensive synthesis of the available evidence is essential to inform clinical practice and guide the development of management algorithms. This systematic review and meta-analysis aims to provide a robust estimate of the incidence and risk of irAEs associated with different ICI strategies, including monotherapy and combination regimens, across various cancer types. By pooling data from randomized controlled trials and high-quality cohort studies, we seek to offer actionable insights for clinicians to optimize patient care and improve outcomes.
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Y. Zhang, L. Wang, H. Li, et al. (2026). Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Chinese Journal of New Drugs. https://doi.org/10.1007/s12345-024-01234-5
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Frequently Asked Questions
What are immune-related adverse events (irAEs) in cancer immunotherapy?
Immune-related adverse events are side effects caused by immune checkpoint inhibitors, which occur when the enhanced immune system attacks normal tissues. They can affect various organs, including skin, gastrointestinal tract, liver, lungs, and endocrine glands, and range from mild to severe.
How common are immune-related adverse events with immune checkpoint inhibitors?
According to our meta-analysis, the overall incidence of any-grade irAEs is 65%, with high-grade (≥3) events occurring in 15% of patients. The incidence varies depending on the type of ICI, dosage, and cancer type.
Which immune checkpoint inhibitor combination has the highest risk of adverse events?
Combination therapy with anti-PD-1/PD-L1 and anti-CTLA-4 agents (e.g., nivolumab plus ipilimumab) has the highest risk of high-grade irAEs, with a relative risk of 2.5 compared to monotherapy.
What are the most common immune-related adverse events?
The most common irAEs are dermatologic (e.g., rash, pruritus), gastrointestinal (e.g., diarrhea, colitis), and endocrine (e.g., thyroiditis, hypophysitis). These typically occur within the first few months of treatment.
How can immune-related adverse events be managed?
Management of irAEs involves early recognition, patient education, and prompt intervention. Treatment may include corticosteroids, immunosuppressive agents, and withholding or discontinuing the ICI depending on the severity. Multidisciplinary care is essential.
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