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.

Keywords: Adverse events; Immunotherapy; Therapeutic intervention; Toxicity burden; immune checkpoint inhibitors.

Fig. 1

Flow chart of irAE studies for seven FDA-approved ICIs: ICI toxicity burden causing tissue or organ disorders may exacerbate ICI-associated irAEs

Fig. 2

Distribution of irAE cases among patients treated with seven FDA-approved ICIs according to the FDA dataset in the past seven years. A-C irAE cases for each ICI were divided into seven outcome groups, including died, disabled, hospitalized, life-threatening, non-serious, required intervention and other outcomes. The total percentage for each outcome group is indicated for ICIs targeting PD1, PDL1 and CTLA4 in (A), (B) and (C), respectively. D Comparison of the rate of hospitalization among patients treated with each ICI. E Proportions of serious irAEs or deaths for each FDA-approved ICI in the FDA dataset (left) and summary of statistical analysis of odds ratio (OR) for seven FDA-approved ICIs (right)

Fig. 3

Total irAE cases and serious irAE cases for seven FDA-approved ICIs among various cancer types. A Total number of irAE cases for seven FDA-approved ICIs: patients with lung cancer ranked first or second for the highest number of total irAEs. B Number of serious irAEs for seven FDA-approved ICIs: patients with lung cancer also ranked first or second for serious irAEs

Fig. 4

Number of irAEs grouped by 18 tissue or organ disorders for FDA-approved ICIs. Nivolumab, pembrolizumab and atezolizumab had the highest case numbers of serious irAEs. “Respiratory, thoracic and mediastinal disorders” was consistently among the top 3 for each ICI

Fig. 5

Correlation between irAEs and 18 tissue or organ disorders in different patient age groups. Correlations for ICIs targeting PD1, PDL1 and CTLA4 are shown in (A), (B) and (C), respectively

Fig. 6

Correlation between irAEs and 18 tissue or organ disorders in different patient sex groups Correlations for ICIs targeting PD1, PDL1 and CTLA4 are shown in (A), (B) and (C), respectively

Fig. 7

Expression of PDCD1 (encoding PD1), CD274 (encoding PD-L1) and CLTA4 in human tissues (including female and male). Tissue-specific gene expression for PDCD1, CD274 and CTLA4 are shown in (A), (B) and (C), respectively. These three genes are highly expressed in lung tissues regardless of sex