Background: Trametinib, an oral MEK1/2 inhibitor, holds promise for tumors that frequently harbor RAS activating mutations, such as pancreatic cancer. Trametinib monotherapy or in combination with gemcitabine showed preliminary activity in patients (pts) with advanced pancreatic cancer. Methods: Eligible pts with untreated metastatic pancreatic cancer were randomized (double-blind, 1:1) to receive gemcitabine 1000 mg/m² intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks, plus either trametinib 2 mg or placebo daily. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR). OS and ORR were also analyzed based on baseline KRAS status as determined in plasma cell free DNA (cfDNA). Results: Baseline characteristics for the 160 randomized and treated pts were similar across arms. Skin related events (73% vs. 34%), diarrhea (54% vs. 28%), thrombocytopenia (40% vs. 28%), and stomatitis (36% vs. 8%) were more frequent with trametinib, as was grade 3/4 anemia (22% vs. 11%). However, rates of grade ≥ 3 thrombocytopenia, neutropenia and febrile neutropenia were similar between the arms. More pts on trametinib arm required dose reduction or interruption due to AEs (68% vs. 49% and 74% vs. 43%, respectively). Median OS was 8.4 months with trametinib compared to 6.7 months with placebo [HR 0.98 (95% CI: 0.67, 1.44, p=0.453)]. Median PFS was 16 weeks on trametinib and 15 weeks on placebo arm. ORRs and median DoRs were 22% and 23.9 weeks and 18% and 16.1 weeks on trametinib and placebo arm, respectively. The median OS and ORR in the subgroup of pts with KRAS mutations (n=143) was similar to OS and ORR for all randomized pts. Conclusions: This is first randomized, placebo-controlled trial evaluating the combination of gemcitabine with a MEK inhibitor. There was an increased incidence of skin, GI, and hematologic toxicities with trametinib compared to placebo. The addition of trametinib did not improve OS, PFS, or response rate. These outcomes remained independent of KRAS mutations based on cfDNA. Clinical trial information: NCT01231581.