Background: Over 90% of pancreatic cancers (PC) have mutant KRAS that is at present not druggable. Activating mutations lead to signaling through RAF/MEK/ERK and PI3K/AKT/mTOR pathways leading to cell growth, proliferation and survival. Pre-clinical data suggest that simultaneously blockade of these pathways is effective in treating KRASmutant tumors. Our trial evaluated this novel, molecularly targeted treatment approach in pancreatic cancer versus mFOLFOX chemotherapy. Methods: 113 pts (PS 0-1) with metastatic PC failing gemcitabine-based therapy were randomized to MK-2206 135 mg weekly plus selumetinib 100 mg daily (MS) or mFOLFOX6 (without bolus 5FU) every 2 weeks. Overall survival (OS) was the primary endpoint with secondary objectives evaluating toxicities, objective tumor response and progression free survival (PFS). Results: Pt characteristics and results are in the table. 34 pts had grade 3 toxicities in the MS arm vs. 19 in the mFOLFOX arm. The most common grade 3 toxicities in the MS arm include rash, mucositis, dehydration and fatigue while for mFOLFOX arm, hematologic toxicities, fatigue, nausea and vomiting. In the MS arm vs. mFOLFOX, there were 0 vs 3 pts with a partial response and 8 vs 9 pts with stable disease, respectively. Shorter survival was observed in the MS arm (median OS 4.0 vs 7.5 mos, hazard ratio (HR) 1.46, 95% CI 0.90-2.38; median PFS 2 mos for each, HR 1.43, 95% CI 0.93-2.20). Approximately 50% of the patients on the mFOLFOX arm went on to receive additional therapy as compared to 30% on the MS arm. Conclusions: MS did not improve OS in pts who previously failed gemcitabine chemotherapy. Collected tissue will be analyzed for potential biomarkers. Clinical trial information: NCT01658943