Comparative efficacy and safety of novel agents versus standard chemotherapy in first-line (1L) locally advanced or metastatic triple-negative breast cancer (TNBC): A systematic review and network meta-analyses.

Abstract

e13124 Background: Survival outcomes for patients with advanced TNBC remain poor. Several novel agents, including antibody–drug conjugates (ADC), immunotherapy, and targeted therapies, have demonstrated activity in 1L locally advanced or metastatic TNBC. We conducted a network meta-analysis to evaluate comparative efficacy and safety of novel agents against SC. Methods: MEDLINE, EMBASE, and SCOPUS were searched for phase II/III randomized trials comparing novel agents with SC in 1L locally advanced or metastatic TNBC through January 21, 2026. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and any-grade adverse events (AEs). Frequentist network meta-analysis was performed for time-to-event outcomes. Due to a star-shaped network, heterogeneity could not be reliably estimated. Pairwise random-effects meta-analyses were performed for ORR and safety. All analyses were performed using R (version 2026.01.0 ) employing netmeta and metabin packages. Results: Of 1,673 records identified, six trials comprising 2,409 patients met inclusion criteria.When compared with SC, Datopotamab deruxtecan (Dato-DXd) demonstrated largest relative effect size (P-score 0.80), followed by ipatasertib + SC (0.67), sacituzumab (0.64), atezolizumab + SC (0.54), and capivasertib + SC (0.35); hazard rations are summarised in table1. However, rankings should be interpreted as exploratory given star shaped network. None of the novel agents demonstrated a statistically significant OS benefit compared with SC (Table 01). No statistically significant difference was observed for ORR for novel agents compared to SC (OR 1.0; 95% CI 0.19-5.10). For safety outcomes, all novel agents were associated with higher odds of any-grade AE compared with SC (OR 2.49; 95% CI 1.93-3.21). Conclusions: For our analysis, Dato-DXd demonstrated the most consistent efficacy signal, particularly for PFS. However, no novel strategy showed a statistically significant OS benefit, and ORR effects were highly heterogeneous. While ADC-based and targeted approaches show promising activity, current evidence remains exploratory, and longer follow-up and direct comparative trials are needed to guide optimal treatment selection. Notably, most trials included in this analysis reported improved outcomes in specific biomarker-defined subpopulations, which may not be fully captured in overall population estimates. Treatment Arm (Ref: SC) HR for PFS (95% CI) HR for OS (95% CI) Dato-DXd 0.57 (0.47-0.69) 0.79 (0.49-1.28) Sacituzumab 0.64 (0.52-0.79) Not mature Capivasertib + SC 0.72 (0.62-0.84) 0.8 (0.44-1.17) Ipatasertib + SC 0.60 (0.37-0.98) 0.8 (0.42-1.52) Atezo + SC 0.66 (0.43-1.01) 0.60 (0.31-1.14)