Immune Checkpoint Inhibitor-Induced Insidiously Progressive, Fatal Interstitial Lung Disease

<b>Background/Objectives:</b> Immune checkpoint inhibitors (ICIs) cause interstitial lung diseases (ILDs) as a type of immune-related adverse event (irAE). The characteristics of ICI-ILD are diverse. The objective of this study is to investigate the clinical features of ICI-ILD, with particular emphasis on insidiously progressive ICI-ILD. <b>Methods:</b> We retrospectively analyzed 232 patients with advanced lung cancer who were treated with ICIs (including combination therapy with cytotoxic agents). <b>Results:</b> IrAEs were observed in 85 patients (36.6%). The most frequent irAE was ICI-ILD (41 patients, 17.7% of all patients). The occurrence of ICI-ILD was associated with a significantly better response compared to the non-irAE group (response rates: 88% vs. 33%), longer progression-free survival (PFS) (median: 17.5 vs. 3.0 months), and longer overall survival (median: 52.6 vs. 16.6 months), respectively. However, six patients died from ICI-ILD, which could be divided into two patterns: early-onset ICI-ILD in three patients (median PFS: 1.2 months), and insidiously progressive ICI-ILD in three patients. In the latter type, ICI-ILD developed unnoticed, progressed insidiously, and led to respiratory failure (median PFS: 7.2 months). The non-organizing pneumonia pattern and a weak response to corticosteroid therapy were also common findings. On average, six cycles of ICI treatment were administered between the time when ICI-ILD became retrospectively recognizable and the discontinuation of ICI treatment. During this period, C-reactive protein levels and the extent of ILD involvement gradually increased. <b>Conclusions:</b> Insidiously progressive ICI-ILD can lead to fatal outcomes. Early discontinuation of ICIs upon recognition of this type of ICI-ILD may improve patient outcomes.