Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors

Abstract

Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.

Keywords: biomarkers; colitis; immune checkpoint inhibitors; immune related adverse events; pneumonitis; predictors; rechallenge; risk factors.

Figure 1

Risk factors for immune-related adverse events. CTLA4, Cytotoxic T-Lymphocyte Antigen 4; PD-1, Programmed Cell death-1; PD-L1, Programmed death-ligand 1; irAE, immune-related adverse events; HER2i, human epidermal growth factor receptor 2 inhibitors; VEGF, Vascular endothelial growth factor; TKI, Tyrosine Kinase Inhibitor; HLA, Human leukocyte antigen; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; ILD, interstitial lung disease; COPD, Chronic obstructive pulmonary disease; RT, radiation therapy; CKD, chronic kidney disease; AKI, acute kidney injury; PPI, Proton-pump inhibitors; NSAID, nonsteroidal anti-inflammatory drugs; ACE, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; ^#, there is weak evidence for these risk factors.