Unresectable pancreatic cancer is still an extremely dismal prognosis. The conventional therapy using chemotherapy has no real effect on survival and new treatments are needed. EGFR and HER2 have been reported to be implicated and upregulated in pancreatic cancer tumorigenesis. The use of monoclonal antibodies (mAb) targeting these two receptors seems a relevant strategy for a new therapy. In a pre-clinical study, we demonstrated the therapeutic effect of the combination of two humanized Ab used in clinic, trastuzumab (Ab anti-HER2) and matuzumab (Ab anti-EGFR) in vivo in different carcinoma types. This Ab combination induced an important tumoral growth delay associated with some complete responses in two pancreatic carcinoma models expressing low HER2 level and in an ovarian model. Following all these results, a clinical trial is planned in pancreatic cancer.