Lenvatinib as an Initial Treatment in Patients with Intermediate-stage Hepatocellular Carcinoma Beyond up-to-seven Criteria and Child-Pugh A Liver Function: A Proof-of-Concept Study

Abstract

Background: Although transcatheter arterial chemoembolisation (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be more favourable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. Methods: This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected for the study. Propensity score matching was used to adjust for patient demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p < 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p < 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). Conclusion: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides more favorable outcome than TACE.

Transarterial‐ chemoembolization remains an effective therapy for intermediate‐stage hepatocellular carcinoma with preserved liver function

“…Currently, there is only one published report in which lenvatinib was compared with TACE. The ORR, median progression‐free survival, and OS for lenvatinib were 73%, 16 months, and 37.9 months, respectively; those for TACE were 33.3%, 3.0 months, and 21.3 months, retrospectively 35 . These results for TACE were considerably different from our study.…”

Alternating Lenvatinib and Trans-Arterial Therapy Prolongs Overall Survival in Patients with Inter-Mediate Stage HepatoCellular Carcinoma: A Propensity Score Matching Study

“…Although TACE is the standard treatment for intermediate-stage HCC [ 9 ], it is ineffective for suppressing tumor growth in multiple HCC nodules ( 7) when administered alone. LEN is the only first-line agent to demonstrate a survival benefit over TACE in TACE-naive patients out of up-to-seven criteria [ 14 ]. In cases where new nodules exhibiting treatment resistance to LEN are detected, a change from LEN to second-line MTAs is recommended.…”

“…Hiraoka et al reported that ALBI grade is useful for assessing hepatic function and HCC prognosis [ 17 ]. ALBI grade 1 and preserved liver function are associated with OS or response rate in LEN treatment [ 14 ]. Moreover, Lee et al reported that ALBI grade is an important factor associated with survival in patients with intermediate-stage HCC who underwent TACE [ 18 ].…”

“…Lenvatinib (LEN) is one of the MTAs approved for first-line treatment of patients with unresectable advanced HCC in the USA, European Union, Japan, and China, based on the results of the REFLECT trial, a global multicenter randomized phase 3 trial of LEN for HCC [ 13 ]. Kudo et al had previously reported that LEN is associated with better OS than TACE in patients with intermediate-stage HCC beyond the up-to-seven criteria in A Proof-Of-Concept Study [ 14 ]. However, it is also associated with a high rate of adverse events (AEs), which leads to discontinuation of LEN treatment and poor prognosis in patients [ 15 ].…”

Role of Multidisciplinary Care in the Management of Hepatocellular Carcinoma

“…A propensity-weighted analysis by Kudo and colleagues suggested improved survival with use of systemic therapy compared with TACE in patients with HCC beyond up-toseven criteria. 12 Although thought provoking, these data are nonrandomized, prone to residual confounding, and it is unclear if and what would be the optimal tumor burden threshold to consider systemic therapy instead of locoregional therapy. Appropriate patient selection in these cases is critical and must be considered in light of all treatment options.…”