Antitumor activity of CP-4055 is enhanced in combination with bevacizumab, cetuximab, and trastuzumab in human NSCLC xenografts

B287 Background: CP-4055 (cytarabine 5’-elaidic acid ester) is a cytotoxic nucleoside analog with broad preclinical antitumor activity in solid tumors and hematologic cancers. CP-4055 uptake is independent of expression of the equilibriative nucleoside transporters. Currently several clinical studies are being conducted with CP-4055 single agent in patients with solid tumors and refractory leukemias. The monoclonal antibodies (mAbs) bevacizumab, cetuximab and trastuzumab have all exhibited clinical activity when administered in combination with cytotoxic chemotherapy. This study was undertaken to evaluate the combinability of CP-4055 with the monoclonal antibodies in animal tumor models. Methods: The antitumor activity of CP-4055 was tested at MTD (50 mg/kg) and ½ MTD, alone or in combination with bevacizumab (5 mg/kg), cetuximab (20 mg/kg) and trastuzumab (4 mg/kg) in two human NSCLC xenografts, MAKSAX and EKVX in Balb/c nu/nu mice. The EKVX and MAKSAX xenografts were characterized for receptor target expression EGFR, HER-2 and VEGF by immunohistochemistry prior to testing of antitumor activity. A high proportion of the cells in the xenografts MAKSAX and EKVX stained positive for EGFR and HER-2 (+++), and both xenografts stained positive for VEGF (++). Results: The antitumor activity of CP-4055 single agent was of similar magnitude both at MTD and ½ MTD and it was enhanced by adding bevacizumab or trastuzumab and to some extent by cetuximab in the MAKSAX xenograft. In the EKVX model, CP-4055 was highly active as monotherapy and a possible additive effect of combination treatment with each of the mAbs could therefore not be distinguished conclusively. The combination treatment regimens were well tolerated, with no increased toxicity in terms of weight loss compared to monotherapy. Conclusion: Potential activity warrants clinical studies of regimens including CP-4055, in patients eligible for therapy with mAbs.