Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n = 46. Study treatment consisted of erlotinib 100 mg + selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1^o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1^st-line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) > 6 weeks, 10 with SD > 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline > 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no study-related deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.