Treatment‐Related and Immune‐Related Adverse Events Associated With Immune Checkpoint Inhibitor‐Based Combination Therapies for Breast Cancer: A Systematic Review and Meta‐Analysis

Immunotherapy has transformed the therapeutic landscape of breast cancer. Nevertheless, an exhaustive overview of the treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) spectrum of immune checkpoint inhibitor (ICI)-based combination therapies remains lacking. We performed a comprehensive systematic review and meta-analysis comparing chemotherapy, antibody-drug conjugate (ADC) therapy, targeted therapy, immunotherapy, endocrine therapy, radiotherapy, and dual therapy combined with ICIs. The primary outcomes were overall incidence rates and profiles for all-grade and grade 3 or higher TRAEs and irAEs according to random effects models. We identified 8236 records, 100 of which (9192 patients) met the inclusion criteria. For grade ≥ 3 TRAEs, the ICI-based chemotherapy and ICI-based ADC regimens demonstrated equivalent incidence rates, marginally exceeding those observed in the ICI-based targeted therapy group. Analysis of irAEs revealed that ICI-based chemotherapy combinations had a significantly lower incidence than other dual-agent regimens did. In triplet regimens that combined ICIs with chemotherapy plus additional immunotherapy, irAEs rates remained nearly comparable to those of dual therapies. Among the therapeutic regimens analyzed, ICIs combined with multitarget tyrosine kinase inhibitors (mTKIs) presented the highest incidence rates of both all-grade and grade ≥ 3 irAEs. Conversely, combination regimens of ICIs with poly ADP-ribose polymerase (PARP) inhibitors or HER2-targeted monotherapy demonstrated markedly lower risks of irAEs. Our study provides comprehensive data on the TRAEs and irAEs associated with ICI-based combination therapies. These results offer direct and practical references for clinicians to evaluate toxicity profiles and optimize treatment decisions in routine breast cancer care.