Abstract
Lenvatinib (LEN) is a multi-target TKI, which plays a pivotal role in the treatment of advanced hepatocellular carcinoma (HCC). The inevitable occurrence of drug resistance still prevents curative potential and is deleterious for the prognosis, and a growing body of studies is accumulating, which have devoted themselves to unveiling its underlying resistance mechanism and made some progress. The dysregulation of crucial signaling pathways, non-coding RNA and RNA modifications were proven to be associated with LEN resistance. A range of drugs were found to influence LEN therapeutic efficacy. In addition, the superiority of LEN combination therapy has been shown to potentially overcome the limitations of LEN monotherapy in a series of research, and a range of promising indicators for predicting treatment response and prognosis have been discovered in recent years. In this review, we summarize the latest developments in LEN resistance, the efficacy and safety of LEN combination therapy as well as associated indicators, which may provide new insight into its resistance as well as ideas in the treatment of advanced HCC.