Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and in vitro assessment via protein phosphorylation array

Abstract

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group (p < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC 50 of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/ third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular‐targeted agent sequential therapy: A propensity score‐matched analysis

“…However, the most favorable MTA therapy for secondary treatment remains unclear as no head‐to‐head comparisons have been conducted among the MTAs. Moreover, the effectiveness of treatment with LEN after progression following SOR treatment has been reported in retrospective studies 8,9 . In contrast, the therapeutic efficacy and safety of SOR or RAM after disease progression following LEN treatment has been reported in small cohort studies 10,11 .…”

Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib

“…These results reiterate the observation that better hepatic reserve function is associated with the therapeutic effect of LEN. [ 8 – 10 ] It has also been reported that the relative dose intensity (RDI) plays an important role in the therapeutic effect of LEN. [ 8 , 11 , 12 ] In all of our cases, hepatic reserve function was good and the RDI, up to the first imaging evaluation, was high (Case 1: 75%, Case 2: 100%, Case 3: 100%) (Table 1 ).…”

“…[ 8 – 10 ] It has also been reported that the relative dose intensity (RDI) plays an important role in the therapeutic effect of LEN. [ 8 , 11 , 12 ] In all of our cases, hepatic reserve function was good and the RDI, up to the first imaging evaluation, was high (Case 1: 75%, Case 2: 100%, Case 3: 100%) (Table 1 ). Although in BCLC stage B, cTACE/TAE is a standard treatment for unresectable HCC, Arizumi et al and Ogasawara et al reported that the switch from cTACE to SOR significantly improved the OS in patients with intermediate-stage HCC who were refractory to cTACE therapy.…”

Sorafenib as second‐line treatment option after failure of lenvatinib in patients with unresectable hepatocellular carcinoma

“…Thus, there is a possibility that SOR can be used as a therapeutic agent after progression on treatment with LEN. In fact, we have reported that LEN treatment is moderately effective as the second‐line treatment after progression on SOR 14 …”

“…In fact, we have reported that LEN treatment is moderately effective as the second-line treatment after progression on SOR. 14 Therefore, in this study, we aimed to investigate the therapeutic effect and safety of SOR in patients with u-HCC after progression on treatment with LEN.…”