Assessment of Immune-Related Interstitial Lung Disease in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: A Multi-Center Prospective Study

Abstract Introduction Programmed death-1 immune checkpoint inhibitors (ICIs) have been shown to improve survival of non-small cell lung cancer (NSCLC) patients. Upon expansion of clinical administration for a variety of cancers, immure-related adverse events (ir-AEs) have been typically recognized to be associated with ICIs therefore, necessitating the monitoring and management of these patients. Among ir-AEs, immune-related interstitial lung disease (ir-ILD) is a serious complication which interrupts treatment and occasionally, is fatal. However, no prospective studies have investigated incidences of ir-ILD and associated risk factors for its development in the clinical setting. Methods This was a prospective cohort study consisting of NSCLC patients treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests (PFTs), daily dyspnea defined by the modified Medical Research Council (mMRC), and anti-tumor response were assessed. Results Among the 138 NSCLC patients that received anti-PD-1 monotherapy, 20 patients (14.5%) developed ir-ILD within median 51.5 days [29-147: interquartile]. This was approximately three-times higher than those in clinical trials. Eleven patients (55.0%), including all of eight patients with high-grade ir-ILD (≥Grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity (%FVC) and forced expiratory volume in 1.0 second (%FEV1), and daily dyspnea measured by mMRC were identified as risk factors for ir-ILD development. Additionally, combination assessment of %FVC and %FEV1 successfully classified patients at risk for ir-ILD development. Conclusion The incidences of ir-ILD were substantially higher in clinical setting. Assessment of spirometry and daily dyspnea before ICI treatment may be useful to monitor and manage NSCLC patients. Trial Registration This study is registered in the University Hospital Medical Information Network in Japan ( http://www.umin.ac.jp/ctr/index-j.htm . UMIN000021548).