In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, offering new hope to patients with various malignancies. These agents, including antibodies targeting CTLA-4, PD-1, and PD-L1, function by unleashing the immune system to recognize and attack tumor cells. However, as their use becomes widespread, the clinical community is increasingly aware of the immune-related adverse events (irAEs) that accompany such treatments. A groundbreaking retrospective study conducted at a Swiss tertiary referral center has now provided an extensive, real-world analysis of these adverse effects, shedding light on their incidence, severity, and demographic variability.
The study meticulously examined electronic health records (EHR) of 500 patients treated with different ICIs from January 2020 to May 2023. By focusing on antibodies such as pembrolizumab, atezolizumab, nivolumab, durvalumab, and combinations involving ipilimumab, the researchers captured a comprehensive snapshot of immune-related toxicities in everyday clinical practice. Notably, irAEs represent a complex spectrum of inflammation-driven side effects occurring as collateral damage from enhanced immune activation, leading to tissue-specific autoimmunity.
Among these 500 patients, 43.2% experienced at least one irAE, an incidence rate confirming that immune toxicities are frequent complications of ICI therapy. It is particularly significant that almost one-third of those affected developed severe irAEs, defined as grade 3 or higher according to the widely used Common Terminology Criteria for Adverse Events (CTCAE). This grading system standardizes toxicity reporting, allowing clinicians and researchers to objectively assess and compare adverse effects.
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Entity-specific analysis of irAE distribution unveiled that dermatological reactions were the most common, affecting 15.2% of patients. Skin-related manifestations might include rashes, pruritus, and vitiligo, reflecting cutaneous hypersensitivity or autoimmune phenomena instigated by immune system dysregulation. Gastrointestinal irAEs followed closely, present in 13% of the cohort, often manifesting as colitis or diarrhea, which can limit treatment continuation and jeopardize patient outcomes.
Endocrine irAEs accounted for 10.8%, highlighting the susceptibility of hormonal axes to immune-mediated damage. Hypophysitis, thyroiditis, and adrenal insufficiency are among the endocrine disorders recognized as complications, and their often subtle onset necessitates vigilant monitoring. Musculoskeletal irAEs, observed in 4.8% of patients, may cause inflammatory arthritis or myositis, contributing to significant morbidity.
Pulmonary toxicities, present in 3.8%, which encompass pneumonitis and interstitial lung inflammation, represent a potentially life-threatening subset of irAEs demanding prompt recognition and intervention. Systemic effects (3.6%) and neurological complications (2.6%), although less frequent, underscore the broad and unpredictable nature of immune-mediated injury. Cardiac, renal, hematological, and ocular irAEs, while rare, also emerged from the data, emphasizing the need for multidisciplinary vigilance.
A remarkable aspect of this study pertained to the gender-related differences in irAE incidence. Females exhibited a higher overall rate of irAEs (47.4%) compared to males (40.5%), with the disparity driven predominantly by a greater incidence of low-grade (grade 1) events. This gender-specific trend invites further investigation into biological and immunological mechanisms potentially modulating susceptibility to immune-related toxicities.
One of the most pressing challenges highlighted by the analysis was the under-reporting of irAEs in coded medical diagnoses. Approximately only half of irAEs identified in the detailed EHR review were formally documented via coding systems. This gap in structured data capture could impede clinical decision-making, epidemiologic surveillance, and the development of predictive algorithms for irAE risk stratification.
This study’s retrospective design, while limiting causal inferences, offers invaluable real-world insights distinct from controlled clinical trial environments. It underscores the benefits of structured, prospective data collection on irAEs to better understand their pathophysiology, optimize management guidelines, and ultimately tailor immunotherapy choices to individual patient profiles.
Regular monitoring and interdisciplinary collaboration emerged as critical prerequisites for managing patients undergoing immune checkpoint blockade. Dermatologists, endocrinologists, pulmonologists, and other specialists are increasingly integral to comprehensive care teams, ensuring prompt diagnosis and treatment of irAEs to maintain the delicate balance between therapeutic efficacy and patient safety.
The study reinforces the imperative for oncologists to educate patients about potential symptoms indicating irAEs and establish robust follow-up protocols. Early recognition and timely administration of immunosuppressive therapies such as corticosteroids can mitigate severe complications, avoid treatment discontinuation, and preserve clinical benefits.
Moreover, the heterogeneous incidence and presentation of irAEs elucidated by this analysis illuminate the complexity of immune system modulation. The wide range of affected organ systems challenges clinicians to remain alert to diverse clinical manifestations, some of which may mimic disease progression or other comorbidities.
Looking forward, the integration of real-world data with advanced biomarker research promises to refine predictive models for irAE development. Genetic, cellular, and molecular profiling may eventually allow pre-emptive identification of high-risk patients, enabling personalized immunotherapy regimens with minimized toxicity.
In conclusion, this extensive real-world evaluation of immune checkpoint inhibitor-related adverse drug events highlights an urgent need for structured monitoring, better documentation, and gender-specific considerations in patient management. As cancer immunotherapy evolves, balancing anti-tumor immunity with immune tolerance will remain paramount in optimizing patient outcomes and transforming the future landscape of oncology care.
Subject of Research: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors in cancer patients, analyzed through retrospective real-world clinical data.
Article Title: Adverse drug events of immune checkpoint inhibitors – a retrospective, descriptive real-world data analysis
Article References: Auch, L.A.M., Sieber, C., Lehnick, D. et al. Adverse drug events of immune checkpoint inhibitors – a retrospective, descriptive real-world data analysis. BMC Cancer 25, 1303 (2025). https://doi.org/10.1186/s12885-025-14733-5
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14733-5
Tags: cancer therapy advancementsCTLA-4 PD-1 PD-L1 antibodiesdemographic variability immune reactionselectronic health records cancer patientsimmune checkpoint inhibitorsimmune-related adverse eventsincidence rate severe side effectsinflammation-driven side effectspembrolizumab atezolizumab nivolumabreal-world analysis irAEsretrospective study immune toxicitiestissue-specific autoimmunity