Background: TGFβ signaling is associated with HCC progression. Inhibition of TGFβ R1 potentiates activity of sorafenib in in-vitro and in-vivo models. Here we report the clinical activity of galunisertib (G) plus sorafenib (S) in pts with incurable HCC and no prior systemic therapy. Methods: Eligibility criteria included incurable HCC with measurable disease per RECIST 1.1, no prior systemic therapy, Child Pugh A, ECOG PS ≤1.G was administered as 80 mg PO BID (lead-in Cohort 1) or 150 mg PO BID (lead-in Cohort 2 and expansion cohort), as intermittent dosing of 14 days on/off (28 days = 1 cycle). S was administered continuously as a 400 mg PO BID. Primary objective was to characterize time-to-progression (TTP) and biomarker changes in pts. Secondary objectives included evaluation of OS, PK, and toxicity (CTCAE v 4.0). Results: 47 pts were enrolled (Cohort 1 = 3, Cohort 2 and expansion cohort = 44). In the 150 mg BID cohort: Male = 88.6%; median age = 64 years; PS = 0/1, 81.8%/18.2%; etiology: hepatitis C = 34.1%, hepatitis B = 18.2%, alcohol = 20.5%, multiple = 13.6%; AFP≥200 µg/L = 50%; portal vein invasion = 34.1%. Incidence of AEs was similar between G dose levels. Overall in the 150mg BID cohort, treatment related AEs ( > 15%) were hand and foot syndrome (61.4%), diarrhea (40.9%), pruritus (22.7%), anemia and weight loss (20.5%), fatigue (29.5%), alopecia (18.2%), myalgia (22.7%), decrease in platelet count and nausea (15.9%). Two pts on 150 mg BID discontinued treatment due to study drug related AEs (anemia and weight loss). PK of G at 150 mg BID (n = 12) when co-administered with S, was similar to that observed in the G monotherapy study. G was rapidly absorbed and had an elimination half-life of approximately 8h. Median TTP (RECIST) was 4.1 (2.8, 5.5) months. OS, with a high censor rate of 55% was not mature at the time of this data cutoff. Median OS was 17.9 (14.8, NE) months. Conclusions: The combination of G plus S demonstrated acceptable safety and a meaningful OS of 17.9 months in an advanced HCC population. TTP was similar to S monotherapy in contemporary clinical trials though interpretation is limited by single arm design. Clinical trial information: NCT01246986