Abstract 3055: Xentuzumab, a humanized IGF-1 and IGF-2 ligand co-neutralizing monoclonal antibody, shows efficacy in a human breast cancer model of bone metastasis

Bone metastases are a frequent complication of cancer and are associated with considerable morbidity. Bones provide a permissive environment for metastatic colonization due to their dynamic turnover and an abundance of secreted factors that are required for bone maintenance. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. IGFs also promote cancer progression, aggressiveness, and treatment resistance via activation of the IGF-1 receptor (IGF-1R) and insulin receptor variant A (IR-A). Of specific relevance to bone metastases, excessive bone destruction in osteolytic metastatic lesions leads to a release of IGF-1 from the bone matrix, thus promoting proliferation of metastatic tumor cells, stimulating tumor cell homing to bones, and contributing to further enhancement of bone destruction. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. The aim of this study was to explore the efficacy of the IGF-1/-2 ligand blocking antibody, xentuzumab (BI 836845[1]), alone and in combination with the mTOR inhibitor everolimus, in a breast cancer bone metastasis xenograft model. MDA-231-BoM cells[2], a subline of MDA-MB-231 selected in vivo for enhanced metastatic ability to bone, were injected intra-cardiacly to form bone metastases, and via tail vein to form lung/visceral metastases and treated with xentuzumab, everolimus, and the combination thereof. Tumor burden was monitored by bioluminescence imaging, and metastasis-associated osteolysis was measured by quantitative bone micro-computed tomography. Tumor-associated morbidity was evaluated by a multi-parameter health scoring scheme. Metastatic tumor burden in the bone was significantly reduced upon treatment with xentuzumab in monotherapy and in combination with everolimus vs. placebo. Xentuzumab (±everolimus) reduced the number and size of osteolytic lesions, delayed and diminished bone metastasis-associated morbidity, and prolonged survival. In contrast, the growth of lung/visceral metastases developing upon intravenous injection of tumor cells was not inhibited by xentuzumab. In summary, the IGF-1/-2 neutralizing antibody xentuzumab showed efficacy in a breast cancer bone metastasis model (with and without everolimus) but did not affect metastatic tumor growth in lung/visceral organs. A phase II trial evaluating the xentuzumab/ everolimus/ exemestane triple combina