Real-World Safety of Immune Checkpoint Inhibitors in Small Cell Lung Cancer: A Systematic Review of Comparative Cohort Studies

Immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in small cell lung cancer (SCLC). However, ICIs can cause treatment-related adverse events (TRAEs), particularly immune-related adverse events (irAEs), which may compromise treatment efficacy and patient quality of life. Most ICI safety data is derived from clinical trials, which may not reflect real-world populations. This systematic review evaluated the real-world safety of ICIs compared to other therapies in SCLC. A systematic search of MEDLINE, Embase, Scopus, CINAHL was conducted from inception to July 21, 2025. Eligible studies were observational cohort studies reporting safety outcomes for ICIs versus other cancer therapies (e.g., chemotherapy, targeted therapy) in SCLC. Study quality was assessed using the Newcastle-Ottawa Scale. A narrative synthesis was conducted to summarise key findings. Twenty retrospective cohort studies were included, all using electronic health record data. Cohort sizes ranged from 14 to 188 patients. Nineteen studies were rated as poor quality due to inadequate adjustment for confounding variables. Across studies, TRAE incidence was comparable between ICI plus chemotherapy combination and chemotherapy alone. Similarly, TRAE and irAE rates were consistent across different ICI plus chemotherapy regimens. Evidence comparing ICIs to targeted therapy was limited. Real-world evidence suggests that adding ICIs to chemotherapy does not substantially increase toxicity in patients with SCLC, and safety profiles are generally consistent across ICI regimens. However, findings are constrained by small sample sizes and poor methodological quality. High-quality, large-scale observational studies are needed to validate these results and better inform clinical decision-making.