Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond

Abstract

Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

“…However, treatment of both, i.e., RR-DTC and HCC, with lenvatinib was associated with more frequently occurring severe adverse effects, especially hypertension and proteinuria [ 28 , 29 , 30 ]. It should be noted that generally adverse events lead to dose reduction or discontinuation of treatment more frequently in cases of lenvatinib than ofsorafenib [ 9 ].…”

“…It acts by inhibiting the kinase activities of VEGFR1-3, fibroblast growth factor receptors family (FGFR) 1-4, platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET [ 3 ]. Lenvatinib treatment of HCC and RR-DTC is associated with a longer progression-free survival than treatment with sorafenib [ 8 , 9 ].…”

An overview: Management of patients with advanced hepatocellular carcinoma

“…The ORR to STRIDE was 20.1%, which was higher than that for sorafenib alone (5.1%). T300 + D1500 is a promising treatment strategy for patients with HCC who are not eligible for atezolizumab plus bevacizumab (109).…”

“…Combination therapies with TKIs, ICIs, and conventional therapies have actually revolutionized the management of advanced HCC because of their marked curative effect. However, combination therapies (and especially those including more than 1 systemic therapy) are accompanied by increased toxicities and each combination strategy may cause different adverse events (109).…”

Challenges and Future Trends of Hepatocellular Carcinoma Immunotherapy

“…The role of another immune-based combination including two ICIs, the PD-L1 inhibitor durvalumab and the anti-CTLA-4 antibody tremelimumab, has been explored in the HIMALAYA trial ( Figure 1 ) [ 21 , 22 , 23 ]. In this open-label, multicenter, phase III study, median OS was 16.4 months in patients receiving durvalumab plus tremelimumab versus 13.8 months in the sorafenib monotherapy arm, whereas no significant differences were reported in median PFS.…”