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Chapter 228Introduction In the Western world, approximately 5% of cancer mortality is due to pancreatic ductal adenocarcinoma (PDAC). At presentation, only 10% to 20% of patients with PDAC have localized disease that can be considered for resection. The remaining patients cannot be cured with resection due to locally advanced pancreatic cancer (LAPC; approximately 35%) or metastatic disease. Treatment of LAPC is extremely challenging. Despite recent advances in the treatment of metastatic pancreatic cancer using combination chemotherapy (CHT) regimens, including oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX; ref. 1), or gemcitabine%u2013paclitaxel protein bound (2), not much progress has been made in the treatment of LAPC in the last decade. Because both metastatic spread and locoregional disease progression are of major concern, combinations of systemic CHT and radiotherapy (RT) are often used. Numerous chemoradiotherapy (CRT) studies have been performed, attempting to postpone disease progression and also to increase the possibility of resection (3, 4). Results of these CRT regimens are comparable, and do not consistently show benefit of combination treatment or from CHT alone (5). However, a recent meta-analysis including 15 randomized trials in which CRT with RT or CHT alone were compared for LAPC showed superiority of CRT in 6- and 12- month survival at the expense of more toxicity (6). Survival at 18 months was not significantly different. Ongoing developments include the use of CRT regimens based upon full dose CHT with added radiation, rather than the other way round (7, 8) or to add additional drugs to improve outcome of CRT (9). Although CRT is considered as standard treatment for LAPC, improvement in efficacy and reduction of toxicity is urgently needed. The epidermal growth factor receptor (EGFR; also known as ErbB-1 and HER1 in humans) signalling cascade plays an important role in the biology of various malignancies, including pancreatic cancer. Human pancreatic cancer cells overexpress EGFR and its known ligands (10, 11), which is correlated with rapidly progressive disease (12). EGFR inhibition by the addition of erlotinib, a tyrosine kinase inhibitor, to gemcitabine is associated with a modest survival benefit in PDAC (13). In colorectal cancer, the clinical efficacy of antibodies against EGFR is restricted to patients with wild-type RAS tumors (14, 15). PDAC is known for its high K-RAS mutation phenotype (>90%) and harbors the highest reported incidence of RAS mutations among all human cancers (16). These mutations rarely