Aberrant c-Met activity has been implicated in the development of hepatocellular 
carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic 
potential. However, clinical trials of nonselective kinase inhibitors with c-Met 
activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with 
HCC have failed so far to demonstrate significant efficacy. This lack of 
observed efficacy is likely due to several factors, including trial design, lack 
of patient selection according to tumor c-Met status, and the prevalent 
off-target activity of these agents, which may indicate that c-Met inhibition is 
incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can 
be dosed at a level predicted to achieve complete inhibition of tumor c-Met 
activity. Moreover, results from early trials can be used to optimize the design 
of clinical trials of these agents. Preliminary results suggest that selective 
c-Met inhibitors have antitumor activity in HCC, with acceptable safety and 
tolerability in patients with Child-Pugh A liver function. Ongoing trials have 
been designed to assess the efficacy and safety of selective c-Met inhibition 
compared with standard therapy in patients with HCC that were selected based on 
tumor c-Met status. Thus, c-Met inhibition continues to be an active area of 
research in HCC, with well-designed trials in progress to investigate the 
benefit of selective c-Met inhibitors. (Hepatology 2018;67:1132-1149).