Efficacy and immune-related adverse events of pembrolizumab with bone-modifying agents in female patients with breast cancer

BACKGROUND: Emerging studies demonstrate that some bone-modifying agents (BMAs), such as denosumab (Dmab), can modulate immune responses by increasing tumor-infiltrating T cells and expanding the T-cell repertoire. Female patients with breast cancer in particular often receive concurrent treatment with immune checkpoint inhibitors (ICI) and BMAs. However, the clinical impact of BMAs on immune-related adverse events (irAE) and cancer outcomes in patients treated with ICI remains poorly understood. MATERIALS AND METHODS: Female patients with breast cancer treated with pembrolizumab between 2017 and 2024 were included. Patients were categorized according to BMA received: zoledronic acid (ZA), Dmab, or none. BMA therapy was considered received within a dose interval prior to ICI (12 months for ZA; 6 months for Dmab), during ICI therapy, or within 1 month of the last ICI dose. RESULTS: In a cohort of 425 female patients with breast cancer treated with pembrolizumab, 55 (12.9%) received Dmab, 31 (7.3%) received ZA, and 339 (80.0%) received no BMA. A total of 255 (60%) patients had early-stage breast cancer, and 170 (40%) had metastatic disease. After a median follow-up of 19.4 months (95% CI, 17.5-20.8), the incidence of severe irAE was higher in patients who received Dmab vs those who received no BMA (21.8% vs 11.5%, P = .04). Patients who received Dmab had higher responses (48.0%) compared to those who received ZA (31.6%) and no BMA (35.0%), although not statistically significant (P = .3). CONCLUSION: This is the first study to suggest an increased rate of severe irAE and potential synergistic anti-tumor effect of Dmab in combination with ICI in female patients with breast cancer.