A Comparison of Lenvatinib versus Sorafenib in the First-Line Treatment of Unresectable Hepatocellular Carcinoma: Selection Criteria to Guide Physician’s Choice in a New Therapeutic Scenario

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common malignancy across the world. Alongside improvement in local approaches for early stages, the prognosis of patients with advanced disease remains poor. The tyrosine kinase inhibitor sorafenib was the first drug approved for advanced HCC. During the past decade, this has been extensively explored in real-life settings, such as Eastern Cooperative Oncology Group performance status 2, Child-Pugh B liver function, chronic kidney disease, HIV infection, transplant recipients and the elderly. After 10 years, the multikinase inhibitor lenvatinib was approved in first-line setting. The Phase III REFLECT trial established the non-inferiority of lenvatinib compared with sorafenib in terms of overall survival, meanwhile exploratory analysis suggests a potential benefit over sorafenib for patients with HBV chronic infection and positive alpha-fetoprotein value. Experience with lenvatinib for patients not matching the REFLECT trial criteria remains promising but still retrospective. Indeed, the treatment sequence after lenvatinib still remains a crucial issue, considering that standard second-line options were tested only in patients who progressed to sorafenib. Overall, the choice between lenvatinib and sorafenib should take into account key selection criteria from randomized trials, evidence to date in special clinical situations, the physician’s experience and patient’s preference. Fast approval of atezolizumab plus bevacizumab as first-line treatment for advanced HCC brought an additional element in this scenario. Undoubtedly, lenvatinib and sorafenib remain available options for patients who are not suitable or those progressed to combination immunotherapy. It is conceivable that new systemic options will contribute to design a new treatment algorithm for HCC in the near future. Meanwhile, prospective studies and biomarker analysis are needed to help physicians in the choice between lenvatinib and sorafenib.

Treatment options for unresectable hepatocellular carcinoma

“…20 Lenvatinib targets several receptors as Tyrosine Kinase Inhibitors (TKI), namely VEGFR 1-3, PDGFR-α, Fibroblast Growth Factor Receptor 1-4 (FGFR 1-4), KIT, and Rearrangement During Transfection (RET). 21 Lenvatinib is used as a first-line treatment and as a second-line treatment for HCC unresectable patients who are intolerant to sorafenib and third-line therapy if sorafenib and regorafenib fail due to the success, tolerability, and cost-effectiveness of Lenvatinib. 22 Patients with Lenvatinib treatment had an average overall survival of 13.6 months.…”

An Update on Hepatocellular Carcinoma in Chronic Kidney Disease

“…The prognosis of patients with HCC at advanced stage remains poor despite improvements in local approaches (surgery and interventional radiology) or liver transplantation (in selected candidates) for early or intermediate stages of HCC. The first drug approved for advanced HCC was the tyrosine kinase inhibitor sorafenib: it has been used a first-line treatment for HCC [ 39 ]. The efficacy and safety of sorafenib has been successfully tested in various phase III and real-life studies including CKD population.…”

Systemic treatment in patients with Child–Pugh B liver dysfunction and advanced hepatocellular carcinoma

“…In a Phase 2 study, patients with ALBI 2 had a time to treatment failure of 5.3 months and a higher rate of AE‐related treatment discontinuation than patients with ALBI 1 ( p < 0.01) 49 . There are no Phase 3 data to support the use of lenvatinib in patients with CP B; sorafenib is often used as the first‐line treatment in this population 50 . In a retrospective cohort study of patients receiving either sorafenib or lenvatinib as first‐line treatment, those with baseline ALBI 2B had a longer median overall treatment duration (4.5 months) than patients with baseline ALBI 3 (3.0 months) 38 …”