Systemic Treatment for Advanced Hepatocellular Carcinoma

Abstract

Background: Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis. First-line sorafenib has been the standard of care for a decade, but the treatment landscape is expanding. This review provides a practical overview of current and future systemic treatment options for advanced HCC and their place in clinical practice.

Summary: First-line sorafenib and lenvatinib have shown to improve the survival of patients with advanced HCC. In the second line, regorafenib provides benefit for patients who previously tolerated sorafenib. Anti-PD1 antibodies, nivolumab and pembrolizumab, recently became available for second-line use in the US. Ramucirumab (for patients with α-fetoprotein [AFP] levels ≥400) and cabozantinib present potential future second-line treatment options. Combinations of systemic and locoregional treatment, such as radiofrequency ablation or selective internal radiotherapy, require further research. Precision medicine has not yet been translated into clinical practice, as the most common driver mutations (TERT promoter, CTNNB1, TP53, and ARID1A mutations) have not yet been shown to be suitable therapeutic targets. However, our growing understanding of signaling pathways and efforts in drug development are expected to pave the way for precision medicine in HCC in the future. Evaluating the place for the current and novel systemic treatment options in clinical practice can be challenging due to the diverse toxicity profiles of the treatment options and characteristics of the patient population. Sorafenib data elucidate the effect patient characteristics (such as the performance score, Child-Pugh class, AFP, etiology of the underlying disease, and level of macrovascular invasion and extrahepatic spread) may have on outcomes in advanced stages.

Key messages: Lenvatinib is expected to join sorafenib as a preferred first-line treatment in advanced HCC. In the second line, the treatment of choice, regorafenib, is soon expected to be accompanied by cabozantinib and ramucirumab in patients with AFP ≥400 ng/mL, whereas nivolumab and pembrolizumab present second-line alternatives in the US.

Keywords: Hepatocellular carcinoma; Patient characteristics; Precision medicine; Targeted therapy; Treatment sequence.

Fig. 1

Managements of AEs of systemic treatments for HCC. The purple boxes contain the main AEs related to sorafenib, lenvatinib, regorafenib, and anti-PD1 antibodies, with the percentages of any grade AEs/grade 3–4 AEs (italics). The blue boxes contain suggestions for the management of the AEs. AE, adverse event; NA, not applicable; HFSR, hand-foot-skin reaction; PD1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand.

Fig. 2

Mutational landscape of HCC. This figure depicts the main signaling pathways mutated in liver carcinogenesis. The main driver genes mutated in HCC in each signaling pathway are shown with the percentages of somatic mutations in each gene. Oncogenes are presented in red and tumor suppressor genes in blue. TERT, CCNE1, and MLL4 are also targeted by recurrent somatic HBV insertions. The TERT gene was either mutated in its promoter or amplified (TERT amp.). ALB, albumin; APC, adenomatosis polyposis coli tumor suppressor; APOB, apolipoprotein B; ARID2, AT-rich interactive domain-containing protein 2; ARIDI1A, AT-rich interactive domain-containing protein 1A; ATM, ataxia-telangiectasia mutated; CCNE1, cyclin E1; CDKN2A, cyclin-dependent kinase inhibitor 2A; CTNNB1, Catenin (cadherin-associated protein) beta 1; FBG, fibrinogen beta chain; FGF19, fibroblast growth factor 19; IL6ST, glycoprotein 130; JAK, janus kinase; KEAP1, kelch-like ECH-associated protein 1; MLL, mixed-lineage leukemia; mTOR, mechanistic target of rapamycin; NFE2L2, nuclear factor (erythroid-derived 2)-like 2; RB1, retinoblastoma protein; PIK2CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RPS6KA3, ribosomal protein S6 kinase, 90kDa, polypeptide 3; STAT, signal transducer and activator of transcription; TERT, telomerase reverse transcriptase; TP53, tumor protein p53; TSC1/2, tuberous sclerosis 1/2; VEGFA, vascular endothelial growth factor A.

Fig. 3

Current and future treatment options by line of therapy and patient subgroup. The green boxes contain recommended (future) therapies. The orange boxes contain alternative future treatments, not recommended as first choice based on the current knowledge. No studies on second-line treatment after progression/intolerance to lenvatinib are currently available. * Insufficient data for robust recommendation. ^† Only registered in the US. ^‡ Not registered. BCLC, Barcelona Clinic Liver Cancer; ECOG-PS, Eastern Cooperative Oncology Group performance status; pts, patients; RCT, randomized controlled trial.