Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study

Abstract

Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAes). ici-related interstitial lung disease (ici-iLD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. therefore, early ici-iLD detection and intervention are important for patient safety. However, a risk assessment method for ici-iLD has not been established and the prediction of ici-iLD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ici-iLD occurrence. Immune checkpoint inhibitors (ICIs) are antibodies that inhibit programmed death-1 (PD-1), PD ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which are called immune checkpoint molecules. These molecules negatively regulate the host immunity; thus, the inhibition of these molecules activates the host immunity and exerts cross-organ antitumour effects 1. In the treatment of lung cancer, some clinical trials have revealed that the administration of ICI alone and in combination with cytotoxic anticancer agents resulted in better clinical outcomes than previous standard treatments; thus, the use of ICI significantly improved lung cancer treatment 2-4. However, the activation of the host immunity by ICI leads to characteristic adverse events, known as immune-related adverse events (irAEs), which exhibit profiles different from those caused by cytotoxic anticancer agents 5,6. Therefore, the management of irAEs is essential for an effective ICI treatment. These irAEs affect various organs, such as the skin, endocrine glands, gastrointestinal tract, and liver, but only a few events are fatal because the majority of them can be controlled by adequate treatment 5,7. Specifically, ICI-related interstitial lung disease (ICI-ILD) has a low incidence (1-5%) and a high severity or mortality rate, according to clinical trials (50-60%) 8,9. Patients with lung cancer are known to have relatively higher ICI-ILD rates than those with other cancers 10. A prospective study of patients with lung cancer reported that the incidence of ICI-ILD was 14.5%, which is higher than that in clinical trials 11. ICI-ILD has also been reported to affect the prognosis of patients with lung cancer 11,12 .

Risk factors for adverse events induced by immune checkpoint inhibitors in patients with non-small-cell lung cancer: a systematic review and meta-analysis

“…In the sensitivity analyses excluding the crude ORs, 10 studies were included [25][26][27][28][29][30][31][32][33][34]. Risk factors that could be pooled and were significantly related with the development of irAEs were squamous histology (OR 1.847; CI 95% 1.048-3.256), a higher number of pack-years of smoked tobacco (OR 2.662; CI 95% 1.014-6.989) and the presence of ground glass attenuation in CT imaging (OR 77.1; CI 95% 7.82-760.3) (Supplementary Table 2).…”

Radiomic Phenotypes for Improving Early Prediction of Survival in Stage III Non-Small Cell Lung Cancer Adenocarcinoma after Chemoradiation

“…In this study, we collected a set of continuous and categorical predictors of OS reported in the existing literature. The continuous features were age at diagnosis [38], body mass index (BMI) [39], and smoking pack per year [40]. The categorical features were race [41], gender [38], and Eastern Cooperative Oncology Group (ECOG) performance status at diagnosis [42].…”

Immunotherapy Use in Patients With Lung Cancer and Comorbidities

“…A number of retrospective studies have demonstrated that pre-existing interstitial lung disease (ILD) increases risk of immunemediated pneumonitis in patients receiving ICI (55)(56)(57). A single-center series of 102 patients also showed a trend towards increased risk of ICI-associated pneumonitis in patients with pre-existing chronic obstructive pulmonary disease (COPD) (58). This observation may reflect the inflammatory nature of COPD, which features increased CD8 T-cell numbers and PD-L1 expression (59).…”