OBJECTIVES: This study aimed to synthetize efficacy evidence via a systematic literature review and meta-analysis to enable the comparison of both lenvatinib (LEN) and sorafenib (SOR) to placebo in unresectable hepatocellular (uHCC).

METHODS: EMBASE®, MEDLINE®, MEDLINE® in-process and Cochrane databases were systematically searched through February 2017 for relevant RCTs in 1L uHCC. The search produced prior SOR randomized controlled trials (RCT) conducted versus placebo. Data from a recent phase 3 randomized RCT in which LEN demonstrated significantly better progression free survival (PFS) versus SOR in treatment naive (1L) uHCC patients was also included. A conventional network meta-analysis (NMA) based on PFS and overall survival (OS) was performed using a frequentist random effect NMA programmed in R-3.3.1. PBO was used as the reference treatment.

RESULTS: Three studies met inclusion criteria: the recently completed LEN vs SOR study: (N=954) and two RCTs comparing SOR to PBO: (1) Llovet 2008 (N=602) and (2) Cheng 2009 (N=226). The RCTs were generally comparable with some variability in patient baseline characteristics: age (63, 66, 61), male% (84, 87, 85), ECOG 0-1% (100, 93, 95), Child–Pugh class A% (99, 97, 97) and prior hepatitis B/C% (50/23, 19/28, 73/8), in LEN vs SOR, SOR vs PBO(1) and SOR vs PBO(2), respectively. In the NMA versus PBO, LEN and SOR yielded indirect HRs of 0.38 and 0.58 for PFS, and 0.63 and 0.69 for OS, respectively. Using LEN as a common comparator, SOR and PBO yielded indirect HRs of 1.52 and 2.63 for PFS, and 1.09 and 1.58 for OS, respectively.

CONCLUSIONS: Our NMA demonstrated that for 1L uHCC, both LEN and SOR demonstrated significantly better PFS vs. PBO: a 62% progression risk reduction for LEN versus 42% for SOR.