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Immunotherapy in advanced hepatocellular carcinoma: an evolving space in the systemic treatment paradigm

© Digestive Medicine Research. All rights reserved. Dig Med Res 2020;3:115 | http://dx.doi.org/10.21037/dmr.2020.03.01 Over the past decade, immune checkpoint inhibitors are being increasingly studied and utilized for cancer therapy. Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is currently a rising cause of cancer-related death in the United States (1). Historically, hepatitis B virus infection and hepatitis C virus infection were the most common risk factors for developing HCC (1,2). Currently in the United States, however, metabolic factors, notably diabetes and obesity, have the highest population attributable fraction (3), with HBV and HCV continuing to have the greatest strength of association in the development of HCC (4). The diagnosis of HCC often occurs at late stages in the disease process given its often non-specific presentation, and effective therapies are currently limited. Sorafenib was the first approved multikinase inhibitor for patients with advanced HCC (2). More recently, lenvatinib (oral multikinase inhibitor) has been approved as another first-line option in advanced HCC based on the phase III REFLECT trial (5). For patients with advanced HCC who have been previously treated with sorafenib, cabozantinib (6), regorafenib (7), and ramucirumab (8) have all been FDA approved as standard therapies. Recently the FDA has also given nivolumab and pembrolizumab accelerated approval for use as second-line agents in patients with advanced HCC who had previously received sorafenib based on the results of the checkmate 040 trial. This was a phase 1/2 dose escalation and expansion trial of nivolumab monotherapy in patients with advanced HCC and in both patients who had and had not previously received sorafenib. Nivolumab 3 mg/kg was used in the dose expansion phase. This study showed an objective response rate of 15% in the dose escalation phase and 20% in the dose expansion phase compared to response of 2–3% with sorafenib (2). Feun and colleagues conducted a phase II study in the United States of the efficacy of pembrolizumab as a secondline agent for treatment of advanced HCC in patients who have had disease progression while receiving sorafenib or have been intolerant to or refused sorafenib (9). This study examined patients with advanced HCC having measurable disease defined by the Reponses Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks with CT or MRI imaging performed after every 3 doses (every 9 week). RECIST v1.1 criteria were used to assess disease response. The primary endpoint of this trial was disease control rate (DCR) defined as the percentage of patients who achieved complete response, partial response, or stable disease (no change in tumor size or regression less than 30%) for a period of at least 8 weeks. Secondary endpoints included the duration of progression-free survival (PFS), overall survival (OS), duration of response, and Editorial Commentary