Background: Refametinib is a potent oral allosteric MEK 1/2 inhibitor with single-agent and synergistic activities in combination with gemcitabine in preclinical pancreatic cancer (PC) models. We report the results of a single-arm, open-label, phase 2a study combining refametinib and gemcitabine in advanced PC. Methods: Eligibility criteria included: ECOG PS ≤ 2; locally advanced, unresectable or metastatic pancreatic adenocarcinoma; and no prior systemic therapy. Refametinib was administered 50 mg bid po in combination with gemcitabine (1000 mg/m2 IV weekly for 7 of 8 weeks in C1; 3 of 4 weeks in subsequent cycles). The primary objective was overall response rate (ORR); secondary objectives were duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS) and safety. All responses were confirmed by central independent radiological review. Genetic biomarker analysis was conducted on circulating tumor DNA from plasma samples (BEAMing). Results: Sixty patients were treated: median age 63 yrs, 53% male, 40% PS 0. KRAS mutations were detected in 39 patients (65%). Best overall response was PR in 35% [median DOR 3.8 mo (117 days; 95% CI: 83-265)]; SD in 38%, PD in 10%, and not evaluable in 17% The DCR was 73%. Median TTP was 7.4 mo (224 days; 95% CI: 188, UL ND); median PFS 6.2 mo (190 days; 95% CI: 112-225); OS 8.9 mo (270 days; 95% CI: 200-355). In the KRAS subgroups (mut/WT respectively) the ORR, mPFS and OS were 28%/48% (p=0.136), 4.6/9.0 mo (HR 0.26) and 6.6/18.2 mo (HR 0.27). Full biomarker analysis is being reported separately (Riess et al, this meeting). The most common grade 3-4 TEAEs were neutropenia (43%), thrombocytopenia (22%) anemia (12%), elevations of AST (12%) or ALT (13%), DVT (10%), hypertension (12%), fatigue (15%) and rash acneiform (10%). Conclusions: The combination of refametinib and gemcitabine in advanced PC is active, with an acceptable safety profile. The reported high prevalence of KRAS mutations in PC patients was confirmed by BEAMing. A trend towards improved outcomes (ORR, PFS and OS) in patients with KRAS wild type PC was observed. Clinical trial information: NCT01251640.