Background: RAS/RAF/MEK/ERK (MAPK) signaling pathway is associated with proliferation, progression, and survival of HCC. Preclinical data suggests that activation of MAPK pathway may be one of resistant mechanisms of sorafenib, and the combination of MEK inhibitor and sorafenib can induce synergistic anticancer activity in HCC. We evaluated the safety and efficacy of trametinib (MEK inhibitor) combined with sorafenib in HCC. Methods: This was a phase I single center study with standard 3+3 design for pts with treatment naïve advanced HCC. The primary endpoints are determining dose limiting toxicities (DLT) and maximum tolerated dose (MTD). Secondary endpoints include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Initial plan was to enroll pts in 4 escalating dose levels (dl)—trametinib 1mg daily (qd)/sorafenib 200mg twice daily (bid)(dl 1), trametinib 1.5mg qd/sorafenib 200mg bid (dl 2), trametinib 1.5mg qd/sorafenib 400mg bid (dl 3), trametinib 2mg qd/sorafenib 400mg bid (dl 4). Eligible pts had advanced unresectable HCC, ECOG PS 1, Child-Pugh Score 6, and adequate organ function. Results: 17 pts were treated in 3 different dl of trametinib and sorafenib (3 in dl 1, 8 in dl 2, and 6 in dl 3). Median age was 65 years (range 40-80) with 64.7% male. All pts were evaluated for toxicity, but only 15 were evaluable for DLT. 2 pts were replaced as they came off of study within 1 month (1 pt in dl 3 due to varices unrelated to the study drug, 1 pt in dl 2 for voluntary withdrawal due to side effects). DLT was noted in dl 3 with 2 pts (grade 4 hypertension (HTN) and grade 3 elevated (elev) of bilirubin/AST/ALT > 7 days). Most common grade 3/4 treatment related adverse events were elev AST (47.1%), HTN (23.5%), elev Alk Phos (17.6%), elev ALT (5.9%), elev bilirubin (5.9%), and diarrhea (5.9%). The median PFS was 4.0 months (mo), and median OS was 5.8 mo. 11 pts were evaluable for response after cycle 2 (8 stable disease (SD), 2 disease progression (PD), 1 partial response). 3 pts were evaluable for response after cycle 4 (1 SD, 2 PD). DCR was 63.6%. Conclusions: Trametinib and sorafenib can be safely administered up to trametinib 1.5mg qd and sorafenib 200mg bid for pts with advanced HCC. Clinical trial information: NCT02292173