Immune checkpoint inhibitors combined with chemotherapy vs chemotherapy alone in advanced or metastatic triple-negative breast cancer: a systematic review and random-effects meta-analysis of randomized controlled trials

Randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors (ICIs) in combination with chemotherapy for treating metastatic and locally advancedtriple-negative breast cancer (TNBC) have reported heterogeneous results, particularly for overall survival (OS). We conducted a systematic review and meta-analysis to clarify the efficacy of ICIs plus chemotherapy compared with chemotherapy alone in this setting. We systematically searched PubMed, Embase (Ovid), and the Cochrane Library from inception to April 2025 for RCTs comparing chemotherapy plus ICIs versus chemotherapy plus placebo in metastatic or locally advanced TNBC. Overall survival (OS) and progression-free survival (PFS) were pooled across atezolizumab and pembrolizumab trials using random-effects meta-analysis with the Hartung-Knapp-Sidik-Jonkman method and restricted maximum likelihood estimation. Prespecified subgroup analyses included programmed death-ligand 1 (PD-L1)-positive populations defined by immune cell (IC) expression (IC ≥1%) and SP142 assay use. Sensitivity analyses included leave-one-out analyses. Publication bias was assessed by funnel plot inspection and Egger’s regression test. Quality assessment was performed using the Risk of Bias 2 assessment tool (RoB2). Effect modification by agent/assay pairing was assessed using Meta-regression. Five studies from four RCTs comprising 2,995 patients met inclusion criteria. The addition of ICIs to chemotherapy was associated with a statistically significant improvement in PFS (pooled HR 0.81, 95% CI 0.73–0.91; p = 0.004), with no evidence of between-study heterogeneity (τ 2 = 0; I 2 = 15%). In contrast, no statistically significant improvement in OS was observed (pooled HR 0.90, 95% CI 0.78–1.04; p = 0.14). There was evidence of low-moderate statistical heterogeneity between studies (τ 2 = 0.01; I 2 = 40%; Cochran Q p = 0.11). Treatment effects were consistent across prespecified subgroups. Leave-one-out analyses demonstrated robust pooled estimates. Funnel plots did not show substantial asymmetry. Egger’s regression test showed no statistically significant evidence of small-study effects for overall survival (intercept = −0.27, 95% CI −0.70 to 0.15; p = 0.41) or progression-free survival (intercept = −0.16, 95% CI −0.59 to 0.26; p = 0.84). In patients with metastatic or locally advanced TNBC, ICIs combined with chemotherapy significantly improve PFS, but do not confer a statistically significant OS benefit based on current randomized evidence. These findings support the role of ICIs in improving disease control while highlighting the need for longer follow-up and additional trials to better define long-term survival outcomes. These findings reinforce PFS as a meaningful endpoint for therapeutic decision-making in advanced TNBC.