Efficacy and safety of immunotherapy in driver mutation-negative advanced non-small cell lung cancer: A systematic review and meta-analysis.

Background and objectives Despite substantial research on immunotherapy, its efficacy and safety in treating advanced non-small cell lung cancer (NSCLC) without identifiable driver mutations remain unclear. The objective of this review was to examine the efficacy and safety of immunotherapy, used as monotherapy or alongside chemotherapy, vs. chemotherapy alone in patients with advanced driver mutation-negative NSCLC. Methods A comprehensive literature search of PubMed, Embase, Scopus, and CENTRAL databases was conducted until December 2024. The protocol was registered in PROSPERO (CRD42024585050). Randomised controlled trials (RCTs) evaluating the efficacy and safety of immunotherapy, either as monotherapy or in combination with chemotherapy, compared with chemotherapy alone, were included. A random-effects meta-analysis was performed. Risk of bias was assessed using the Cochrane RoB 2 tool, and the certainty of evidence was evaluated using the GRADE framework. Results Twenty-three RCTs (n=14605 participants) were included. Immunotherapy (± chemotherapy) significantly improved overall survival [22 RCTs; 14,375 participants, hazard ratio (HR): 0.77; 95% Confidence interval (CI): 0.72-0.83] and progression-free survival (22 RCTs; 14,003 participants, HR: 0.67; 95% CI: 0.58-0.76) compared with chemotherapy alone. The objective response rate was also higher with immunotherapy (23 RCTs; 12,967 participants, RR 1.38, 95% CI: 1.24-1.54). No statistically significant differences were observed between the groups in terms of overall adverse event rates. Interpretation and conclusions Immunotherapy, whether administered alone or in combination with chemotherapy, provides significant survival benefits in patients with advanced driver mutation-negative NSCLC.