Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in advanced non-small cell lung cancer: A systematic review of randomized controlled trials

Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for advanced non-small cell lung cancer (NSCLC). This systematic review synthesizes the evidence from randomized controlled trials (RCTs) to evaluate the efficacy and safety of ICI-based therapies compared to chemotherapy. Methods We systematically searched PubMed for RCTs published between January 2015 and January 2026 that compared ICI monotherapy or combinations to chemotherapy in patients with advanced NSCLC. Data on overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results 96 RCTs were included. ICI-based regimens demonstrated a consistent and significant improvement in OS (Hazard Ratio [HR] range: ~0.40–0.79) and PFS (HR range: ~0.37–0.70) compared to chemotherapy. Benefit was observed across lines of therapy, from first-line metastatic to perioperative settings. High PD-L1 expression and tumor mutational burden (TMB) were key predictive biomarkers for greater efficacy. While ICIs were associated with a distinct profile of immune-related AEs, they generally showed a favorable safety profile compared to chemotherapy, with lower rates of severe hematological and gastrointestinal toxicities. Conclusion ICI-based therapies represent a superior standard of care for advanced NSCLC, offering significant and durable survival benefits over chemotherapy. Treatment decisions should be guided by biomarker status and clinical scenario. Future research should focus on long-term outcomes, optimal combination strategies, and managing immune-related toxicity.