High FDG Uptake in the Non-cancerous Lung Predicts Immune-Related Adverse Events and Poor Prognosis in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors.

RATIONALE AND OBJECTIVES: Immune checkpoint inhibitors (ICIs) have improved survival in non-small cell lung cancer (NSCLC); however, predicting immune-related adverse events (irAEs) remains a clinical challenge. We previously showed that high 18F-fluorodeoxyglucose (18F-FDG) uptake in the non-cancerous lung (NCL) on PET/CT is associated with the risk of interstitial lung disease. This study further investigated whether NCL FDG uptake predicts the risk of irAEs, including both ILD and non-ILD events, as well as survival outcomes in patients with lung cancer receiving ICIs. MATERIALS AND METHODS: We retrospectively analyzed 165 patients with lung cancer who underwent PET/CT before ICI therapy. FDG uptake in the NCL, defined as the lung contralateral to the primary tumor and free of metastatic lesions, was quantified using AI-based segmentation. Total glycolytic activity in the NCL (NCL-TGA1.0) was calculated as the product of the mean SUV and the lung volume, both measured within regions with SUV ≥1.0. Associations of NCL-TGA1.0 with irAE incidence and survival outcomes were assessed using multivariable and Kaplan-Meier analyses. RESULTS: High NCL-TGA1.0 (≥149.45) was independently associated with increased risk of irAEs in multivariate analysis (odds ratio [OR]: 6.910; p=0.005), including non-ILD irAEs (OR: 4.244; p=0.020). In survival analysis of 84 unresectable NSCLC patients, high NCL-TGA1.0 was associated with significantly shorter progression-free survival (median: 4.30 vs. 9.90 months, p=0.007) and overall survival (median: 6.93 vs. 22.03 months, p=0.029). CONCLUSION: High FDG uptake in the NCL is a predictor of irAEs and poor survival in patients with lung cancer receiving ICIs. These results may help to identify high-risk patients prior to treatment.