Abstract Background: Both local and systemic recurrences are common after surgical resection of pancreatic ductal adenocarcinoma (PDA). This pattern of failure suggests that a combination of systemic and local adjuvant therapy may positively impact survival. The epidermal growth factor receptor (EGFR) gene is overexpressed in up to 80% of PDA specimens. Thus, EGFR is an attractive target for improving efficacy of adjuvant therapy for PDA. Purpose: (1) To evaluate the antitumor activity of erlotinib (E) combined with standard adjuvant chemoradiotherapy (CRT) and chemotherapy as measured by progression free survival (PFS) and overall survival (OS). (2) To characterize the toxicity profile of E combined with adjuvant therapy. Methods: 43 patients with resected stage I/II PDA were enrolled in a phase II trial of E (100 mg daily) and capecitabine (800 mg/m2 twice daily Monday-Friday) administered concurrently with IMRT delivered at 1.8 Gy daily in 28 fractions (50.4 Gy total). 4–8 weeks following CRT, patients continued treatment with 4 cycles of gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days) and E (100 mg daily). OS and PFS were calculated as time from surgery to death and to disease progression, respectively. Toxicity was assessed using the NCI CTCAE Version 3.0. Results: Mean age was 61.7 years (SD, 8.7) and 44% were male. 72% had tumors of the pancreatic head, while 28% had tumors of the body/tail. 86% had regional nodal involvement and 33% had positive resection margins. Median follow-up was 16.7 months (interquartile range, 7.4–22.8). Median OS was 24.7 months (95% CI, 18.5–30.9). Median PFS was 15.4 months (95% CI, 9.4–21.3). Survival rate at 1 year was 90.3%. Median CA19–9 prior to CRT was 30.6 U/mL; CRT combined with E resulted in CA19–9 reduction or stabilization in 84.8%. No difference in OS was observed between patients with tumors of the pancreatic head versus body/tail (p=0.64). Of 27 patients who progressed, first recurrence developed distantly in 16 (59.3%) and locally in 11 (40.7%). A trend towards greater OS (25.1 vs. 19.0 months) was observed among patients who first recurred locally (p=0.10). CRT was stopped early due to toxicity in 5 patients (11.6%); 11 (25.6%) required a treatment break; and 3 (6.7%) required discontinuation of chemotherapy before completion of CRT. Acute grade 2 toxicity included weight loss (27.9%), abdominal pain/nausea/vomiting (27.9%), anorexia (25.6%), fatigue (23.3%), dermatitis (20.9%), diarrhea (9.3%), and transaminitis (4.7%), but none of these were dose-limiting. Acute grade 3 toxicity included neutropenia (11.6%), transaminitis (7.0%), dermatitis (4.7%), and weight loss (2.3%). 1 patient experienced grade 4 neutropenia during chemotherapy. 3 patients (7.0%) experienced grade ≥3 late toxicity in the form of small bowel obstruction. Conclusions: Preliminary analysis of this phase II trial provides encouraging evidence that E combined with standard adjuvant therapy may improve PFS in patients with resected PDA. Longer follow-up is needed to establish whether the addition of E provides a survival advantage over current standard of care regimens. Acute grade 2 toxicity is considerable, but does not preclude patients from receiving the full dose of RT. Grade ≥3 acute and late toxicities are uncommon, though longer follow-up may be necessary to adequately assess late toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A87.