OBJECTIVE:: To evaluate the toxicity of daily gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, with concurrent chemoradiation (CRT) in patients with locally advanced pancreatic adenocarcinoma and prospectively evaluate plasma k-ras as a potential marker of response to gefitinib and CRT. METHODS:: Eleven of 12 eligible patients enrolled received a 7-day induction of gefitinib (250 mg PO) followed by daily gefitinib with concurrent CRT. Patients received 50.4 Gy/28 fractions of external beam radiation with weekly paclitaxel (40 mg/m IV) followed by maintenance on gefitinib. Plasma k-ras codon 12 mutations were detected using a two-stage restriction fragment length polymorphism-polymerase chain reaction assay on patients' plasma both before and after therapy. Mutations were confirmed by direct sequencing. RESULTS:: Common adverse events included grade 1 skin rash (63%), grade 1 to 2 gastrointestinal symptoms including anorexia, nausea, vomiting, and diarrhea occurred in 63% of patients, grade 3 nausea occurred in 45% of patients. Three patients did not complete therapy, only one was possibly associated with study drug. K-ras mutations were detected in the pre-gefitinib plasma of 5/11 patients and in the matched tumor tissue of 3/4 patients. In patients where k-ras mutations were undetectable post-treatment, survival times were favorable. CONCLUSIONS:: Combination of daily gefitinib with concurrent CRT in this locally advanced pancreatic cancer population was reasonably tolerated. Rapid changes in serum k-ras may provide critical information as to the efficacy of a novel agent and assist in tailoring treatment for cancers of the pancreas.