Advances in Pharmacotherapy of Hepatocellular Carcinoma: A State-of-the-Art Review

Abstract

Background: Due to the number of emerging new treatment options, the systemic treatment of hepatocellular carcinoma (HCC) is rapidly changing. We provide here an overview of the current landscape of systemic treatment of HCC and discuss its potential future development.

Summary: HCC is a leading cause of tumor-related death worldwide. Despite the efforts aimed at reducing the prevalence of HCC through vaccination and antiviral treatment, and the implementation of screening programs for early tumor detection, most patients are diagnosed with or progress to advanced HCC. For approximately 10 years, sorafenib has been the only effective systemic treatment available for these patients. Recently, however, a number of new systemic compounds, comprising several multi-kinase inhibitors and immune-checkpoint inhibitors, have been approved for treatment of HCC. These new agents are opening a plethora of therapeutic options for the future therapy of HCC.

Key messages: The rapid progress in the treatment of HCC raises the question of the optimal combination and sequence of these agents in the treatment of patients with advanced disease. The substantial improvements in terms of objective response and survival indicate that the use of immune-checkpoint inhibitors-based treatment combinations may be extended to patients with intermediate-stage HCC.

Keywords: Hepatocellular carcinoma; Immunotherapy; Pharmacotherapy.

Fig. 1

Sequential treatment of HCC. The figure illustrates the available therapies of HCC and their sequential use. The noninterrupted arrow-lines indicate therapies that were investigated in the illustrated sequence by clinical trials. The interrupted therapies exemplify plausible therapeutic sequences that were not or not accurately investigated in the present form. The box with the dotted lines shows therapies that are approved by the FDA but not by the EMA. Of note is that patients with autoimmune disease, uncontrolled varices, and organ transplant recipients might not be optimal candidates for a first-line therapy with atezo/bev (box with interrupted lines). References: IMbrave150 [9]; SHARP [18]; REFLECT [7]; RESORCE [5]; CELESTIAL [6]; REACH II [8]; CheckMate 040 [29]; Keynote 224 [31]and 240 [32]; CheckMate 040 [33]. HCC, hepatocellular carcinoma; Q2W, every 2 weeks; Q3W, every 3 weeks; EMA, European Medicines Agency.

Fig. 2

Study design of the DEMAND trial. The figure illustrates the study design of the DEMAND trial that will address efficacy of atezo/bev with or without TACE in patients with HCC in stage BCLC-B; *6 weeks after treatment initiation and every 8 weeks thereafter. BCLC, Barcelona-Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; IV, intravenous; MWA, microwave ablation; N, sample size; OS, overall survival; PFS, progression-free survival; Q3W, once every 3 weeks; QoL, quality of life; R, randomization; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; RFA, radiofrequency ablation; SIRT, selective internal radiation treatment; TACE, transarterial chemoembolization. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov) Reference: DEMAND [60].