Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer.

Pancreatic cancer has a very poor prognosis, making it one of the five most common causes of cancer mortality in developed countries. After curative intended resection only 5–10% of patients with adenocarcinoma of the pancreas will be alive at 5 years after diagnosis. Advanced (unresectable locally advanced or metastatic) pancreatic cancer is an incurable disease with limited treatment options. Since more than a decade, the nucleoside analogue gemcitabine is regarded as a standard of care for patients with advanced disease, providing clinical benefit and a moderate improvement in survival (Burris et al, 1997). Several randomised phase III trials failed to show a survival benefit for gemcitabine-based combination chemotherapy so far; however, meta-analytic data suggest a possible survival benefit for the use of fluoropyrimidines including capecitabine in combination with gemcitabine in selected patients, that is, those with metastatic disease and a good performance status (Heinemann et al, 2008). The anti-EGFR tyrosine kinase inhibitor erlotinib was demonstrated to result in superior survival, especially in patients developing skin rash (Moore et al, 2007). HER2 is a related receptor tyrosine kinase encoded by proto-oncogenes. Once activated, the signal-transduction cascade promotes cellular proliferation migration and survival. Immunohistochemical (IHC) overexpression of HER2 in various tumour cells has been not only associated with a poor prognosis, but also offers the therapeutic option of receptor targeting therapies. Studies report HER2 expression in up to 45% of patients with pancreatic cancer (Yamanaka et al, 1993). Targeting HER2 in pancreatic cancer cell lines and a xenograft mouse model showed encouraging results (Buechler et al, 2001, 2005). Therefore, the aim of this study was to clarify the clinical significance of HER2 expression in patients with metastatic pancreatic cancer and to determine the potential of HER2 as therapeutic target in these patients. On the basis of these data, we assessed the activity of the combination of trastuzumab and capecitabine in patients with advanced IHC +3 HER2 expressing pancreatic cancer or HER2 gene amplification. As the outcome of patients with locally advanced and metastatic pancreatic cancer is different and the response assessment in the latter is more reliable, only patients with metastatic disease were included. The objectives of the trial were to determine progression-free survival (PFS) after 12 weeks (primary endpoint), PFS, overall survival (OS), response rate (according to RECIST criteria), clinical benefit response (CBR) and safety profile.