A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer.

PURPOSE: Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. EXPERIMENTAL DESIGN: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. RESULTS: Sixteen patients were recruited median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). CONCLUSIONS: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.