Research in context
Evidence before this study
Patients with advanced hepatocellular carcinoma who have tumours that are not amenable to surgical resection or local treatment have few effective treatment options. Although treatment with multikinase inhibitors provides some overall survival benefit—for example, sorafenib in previously untreated patients and regorafenib in sorafenib progressors—an unmet need remains in many patients. Chronic inflammatory conditions in the liver, such as cirrhosis and viral hepatitis, result in some degree of immunosuppression within the hepatocellular carcinoma tumour microenvironment, making immune checkpoints attractive therapeutic targets. We searched PubMed from Sept 1, 2010, to Sept 1, 2016, for articles using search terms “advanced HCC” and “immunotherapy OR immune checkpoint AND HCC”. Non-English articles, review articles, and meta-analysis references were excluded. We identified one relevant phase 1 clinical trial from 2013 evaluating the cytotoxic T-lymphocyte antigen (CTLA-4) checkpoint inhibitor tremelimumab in a small cohort of patients with advanced hepatocellular carcinoma who were infected with hepatitis C virus (HCV), which reported a manageable safety profile as well as preliminary evidence of antitumour and antiviral activity. Several preclinical studies have provided evidence in support of immunotherapeutic approaches for hepatocellular carcinoma, including the immunogenicity of transformed hepatocytes and immunosuppressive tumour microenvironments containing infiltrating lymphocytes. However, evidence showing the usefulness of immune checkpoint inhibitors in the treatment of patients with advanced hepatocellular carcinoma has been very limited. As early as 2010, reports have shown that programmed cell death protein-1 (PD-1) inhibitors can be potent immuno-oncology agents in patients with metastatic melanoma, providing rationale for immune checkpoint therapies in multiple other malignancies. When the CheckMate 040 trial began in 2012, several trials of nivolumab in metastatic tumour settings were ongoing. Whether liver-related toxicities from immune checkpoint inhibitors would be affected by concomitant HCV or hepatitis B virus (HBV) infection in patients with hepatocellular carcinoma was not known.
Added value of this study
To our knowledge, this is the first report of a PD-1 checkpoint inhibitor in patients with advanced hepatocellular carcinoma. The CheckMate 040 trial is a prospective, non-comparative, phase 1/2 dose study of nivolumab that assessed safety and clinical benefit across multiple hepatocellular carcinoma aetiologies, including patients with HCV or HBV infection. The efficacy of nivolumab monotherapy was evaluated as a first-line treatment in patients who had not previously received sorafenib or were intolerant and as a second-line treatment in those with previous disease progression on sorafenib.
Implications of all the available evidence
Since the CheckMate 040 trial began, nivolumab has been approved in the USA and European Union for the treatment ofmelanoma, refractory non-small cell lung cancer, advancedrenal cell carcinoma, and Hodgkin lymphoma; and squamouscell carcinoma of the head and neck and urothelial carcinoma (only in the USA). Studies have shown that nivolumab monotherapy provides improved overall survival or clinical benefit in these approved indications. In this study in patients with advanced hepatocellular carcinoma, nivolumab showed encouraging objective response rates and overall survival. The safety profile of nivolumab was manageable and no new safety signals were observed. These findings support further investigation of nivolumab as a treatment option for patients with advanced hepatocellular carcinoma; a phase 3 randomised study of nivolumab monotherapy compared with sorafenib is underway.