Background: Treatment for advanced HCC remains limited and outcomes are poor. However, emerging data implicate FGF19 as a key HCC driver and suggest its receptor, FGFR4 as a novel therapeutic target. A phase 1 study (NCT02508467) was initiated to assess the safety and clinical activity of BLU-554, a potent, highly-selective oral FGFR4 inhibitor. Methods: Adult patients (pts) with advanced HCC and well-preserved liver function received BLU-554 once daily on a 4-week cycle following a 3 + 3 escalation/MTD expansion design. Adverse events (AEs) per CTCAE, PK, PD and pathway activation (tumor FGF19 IHC) were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 4/20/17 cutoff, 61 pts have been treated with BLU-554 including 25 in dose escalation (140-900 mg) and 36 in the ongoing dose expansion. 48 (79%) pts had metastatic disease, 54 (89%) had failed ≥1 prior systemic therapy (48 (79%) sorafenib; 11 (18%) nivolumab) and 29 (48%) had pathway activation (IHC+). Based on safety profile, PK, PD, and anti-tumor activity, 600 mg was the MTD and RP2D. Radiographic tumor reduction and objective response per RECIST 1.1 were observed in IHC+ pts in dose escalation and dose expansion. Of 19 IHC+ pts with ≥ 1 radiographic assessment, 11 (58%) pts had tumor reduction: 6 with SD, 4 with PR and 1 with CR (ORR 26%). 6 (32%) IHC+ pts had duration of treatment ≥ 6 months. In contrast, only 4 (15%) of 27 IHC negative pts had tumor reduction (all SD) and only 1 (4%) had duration of treatment ≥ 6 months. Most AEs (regardless of causality) were Grade (Gr) 1-2, including diarrhea (66%), nausea (43%), vomiting (39%), ALT increase (33%), fatigue, AST increase (29% each), abdominal pain (23%), anemia, and decreased appetite (20% each). AST (13%) and ALT (10%) increase, were the only BLU-554-related Gr 3-4 AEs occurring in ≥ 10% of pts. 2 pts experienced DLT (1 Gr 3 abdominal pain; 1 Gr 3 fatigue lasting > 7 days) at 900 mg. 36 (59%) pts have discontinued treatment: 26 disease progression; 5 AE; 3 investigator’s decision; 2 withdrew consent. Conclusions: BLU-554 is well tolerated at the recommended dose of 600 mg and demonstrates important clinical activity in FGF19 IHC+ advanced HCC pts who have failed prior systemic therapy. Clinical trial identification: NCT02508467 Legal entity responsible for the study: Blueprint Medicines Corporation Funding: Blueprint Medicines Corporation Disclosure: D. Sarker: Honoraria: Pfizer, Novartis, Bayer, Ipsen. Advisory board: Blueprint, Baxalta. S.P. Choo: Advisory board +/- honoraria: Norvatis; Celgene; Sirtex, Bristol-Myers Squibb; New Beta-Innovation Oncology; Bio-Cancer Treatment; Research grant: Bristol-Myers Squibb, Sirtex. T. Meyer: Advisory board for Merck, Bristol-Myers Squibb, Bayer and Eisai. Grants from Bayer and BTG. J-H. Yoon: Research grants from Bayer HealthCare Pharmaceuticals, Daewoong Pharmaceuticals, and Bukwang Pharmaceuticals. J-W. Park: Honoraria Support from: Bayer, Merck. Advisory Board of: Bristol-Myers Squibb, Merck. Consulting of: Bristol-Myers Squibb, ONO, Bayer. S. Faivre: Consulting of Bayer, BMS, Lilly, Merck Serono, Novartis. Y-K. Kang: Advisory Board of Blueprint, Novartis, Roche, Merck, Ono, Bristol-Myers Squibb, LSK Biopharma, Daehwa, Taiho. All other authors have declared no conflicts of interest.