Abstract Background: Immune checkpoint inhibitors (ICIs) in combination with chemotherapy, have markedly transformed the therapeutic alogorithm of high risk early-stage triple-negative breast cancer (eTNBC). Although the safety and efficacy of ICIs have been extensively evaluated in randomized clinical trials (RCTs), their toxicity and effectiveness profiles may differ in real-world clinical practice. This systematic review and meta-analysis aimed to compare the incidence of all-grade adverse events (AEs), grade ≥3 AEs, treatment related discontinuation, and pathological complete response (pCR) rates across phase I-III RCTs and real-world evidence (RWE) in patients with eTNBC receiving neoadjuvant ICIs. Methods: Fourteen RCTs and ten RWE studies were included in the analysis. Incidence of all-grade AEs, grade ≥3 AEs, treatment related discontinuation and pCR rate were collected. Proportions were logit-transformed to stabilize variances and pooled using a random-effects model with Hartung-Knapp adjustment. Subgroup differences between RWE and RCTs were evaluated using the Q-test for subgroup analysis. Separate analyses were conducted for pCR, overall AEs, grade ≥3 AEs and treatment discontinuation to explore consistency of findings across different outcomes. Results: The pooled incidence of all-grade AEs was higher in RCTs compared to RWE, with estimates of 93% (95% CI: 78-98%) and 80% (95% CI: 27-98%), respectively. However, the difference between subgroups did not reach statistical significance in the random-effects model (Q = 1.18, p = 0.28). Similarly, the incidence of grade ≥3 AEs was 49% in RCTs (95% CI: 27-71%) versus 30% in RWE (95% CI: 14-52%), with no significant difference observed between groups (Q = 1.85, p = 0.17). Treatment discontinuation rates were consistent across study types, with both RCTs and RWE showing a pooled incidence of 19%, with no difference between subgroups (Q = 0.00, p = 0.97). Regarding pCR, the pooled rate was 58% (95% CI: 53-62%) in RCTs and 54% (95% CI: 43-65%) in RWD, with no statistically significant subgroup difference (Q = 0.46, p = 0.50). Conclusions: The incidence and severity of adverse events and pCR rates, were comparable between randomized clinical trials and real-world evidence, indicating that immunotherapy maintains consistent safety and effectiveness profiles across both contexts. These results reinforce the external validity of trial-derived data for application in routine clinical practice. Ongoing post-marketing surveillance and standardized reporting remain crucial to ensure patient safety, optimize outcomes, and inform evidence-based treatment decisions. Citation Format: A. Longobardi, R. Buonaiuto, C. Calderaio, A. Caltavituro, V. Cantile, G. Crimaldi, F. Puglisi, L. Del Mastro, C. De Angelis, M. De Laurentiis, M. Giuliano, G. Arpino. Safety and Efficacy of Immune Checkpoint Inhibitors in Early Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis of Real-World Evidence vs. Clinical Trial Data abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-13.
Longobardi et al. (2026) studied this question.