Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States

Abstract

Background Immune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients. Methods irAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software. Results irAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. ‘Respiratory, thoracic and mediastinal disorders’ and ‘gastrointestinal disorders’ were the two most common groups of disorders caused by the seven ICIs studied. ‘Cardiac disorders’ was the main type of disorders caused by these ICIs in cancer patients aged 65–85, while ‘reproductive system and breast disease’ was the main type of disorder in cancer patients aged 18–64. ‘Respiratory, thoracic, mediastinal diseases’ and ‘reproductive system and breast diseases’ were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively. Conclusion Tissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

Adverse events of immune checkpoint therapy alone versus when combined with vascular endothelial growth factor inhibitors: a pooled meta-analysis of 1735 patients

“…Only 2 peer-reviewed publications were included, and most studies were available only as abstracts, making it difficult to assess the risk of bias. Additionally, our study assumed that the type of cancer does not impact immunotherapy toxicity, while some studies have suggested that the risk of immunotherapy toxicity may be higher in certain types of cancer, such as lung cancer ( 28 , 29 ). Our analysis only included one RCT that evaluated the safety profile of ICT versus ICT with VEGFi combination therapy in non-small cell lung cancer ( 24 ).…”

Different associations between organ-specific immune-related adverse event and survival in non-small cell lung cancer patients treated with programmed death-1 inhibitors-based combination therapy

“…During ICIs treatment, irAEs occur unpredictably and can be life-threatening. 5,23 It is essential to have a deeper understanding of irAEs in order to effectively manage the benefit-to-risk ratio of ICIs. In this observational study, we evaluated the association between irAEs and response rate and survival in NSCLC patients treated with PD-1 inhibitors-based combination therapy, especially in combination with chemotherapy.…”

Recent research and clinical progress of CTLA-4-based immunotherapy for breast cancer

“…Male patients are more prone to respiratory and thoracic disorders, whereas reproductive system and breast diseases prevail among female patients. The results indicate that sex or age contributes to the occurrence of different irAEs, requiring a heightened awareness of respiratory and genitourinary toxicities for male patients, while female patients need increased prevention of reproductive system toxicities ( 92 ). Additionally, multiple studies have demonstrated that ICIs can induce various dermatological adverse events (DAEs), such as autoimmune bullous dermatosis, acute generalized exanthematous pustulosis, and psoriasiform rash ( 93 ).…”