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

Oncologist. 2025 Jun 4;30(6):oyaf134. doi: 10.1093/oncolo/oyaf134.

Abstract

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.

Keywords: breast cancer; denosumab; immune-related adverse events; immunotherapy; pembrolizumab.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / pharmacology
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Agents, Immunological* / adverse effects
  • Antineoplastic Agents, Immunological* / therapeutic use
  • Bone Density Conservation Agents* / adverse effects
  • Bone Density Conservation Agents* / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / immunology
  • Breast Neoplasms* / pathology
  • Denosumab / adverse effects
  • Denosumab / therapeutic use
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / adverse effects
  • Immune Checkpoint Inhibitors / therapeutic use
  • Middle Aged
  • Zoledronic Acid / adverse effects
  • Zoledronic Acid / therapeutic use

Substances

  • pembrolizumab
  • Antibodies, Monoclonal, Humanized
  • Bone Density Conservation Agents
  • Denosumab
  • Zoledronic Acid
  • Immune Checkpoint Inhibitors
  • Antineoplastic Agents, Immunological