Elsevier

The Lancet

Volume 389, Issue 10088, 24–30 June 2017, Pages 2492-2502
The Lancet

Articles
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

https://doi.org/10.1016/S0140-6736(17)31046-2Get rights and content

Summary

Background

For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis.

Methods

We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1–10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878.

Findings

Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase.

Interpretation

Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.

Funding

Bristol-Myers Squibb.

Introduction

Worldwide, liver cancer accounts for more than 850 000 new cancer cases annually, and approximately 90% of these are hepatocellular carcinoma.1, 2 Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma.3 Hepatocellular carcinoma is often diagnosed at advanced stages of disease for which highly effective therapies are insufficient. At present, sorafenib, a small-molecule multikinase inhibitor, is the only evidence-based systemic treatment option for patients with advanced hepatocellular carcinoma.2, 4, 5 In previously untreated patients with advanced disease, the median overall survival was 10·7 months in those treated with sorafenib and 7·9 months in those who received placebo (hazard ratio [HR] 0·69, 95% CI 0·55–0·87; p<0·001).6 In selected patients who tolerated sorafenib but progressed while on therapy, another multikinase inhibitor, regorafenib, has been reported to provide an overall survival benefit compared with placebo (10·6 months vs 7·8 months; HR 0·62, 95% CI 0·50–0·78; p<0·001).7

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.

Immunotherapies that inhibit the immune checkpoint interaction between programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown substantial survival benefit in some patients with metastatic carcinomas of multiple tissue origins.8, 9, 10, 11 The presence of tumour-infiltrating lymphocytes expressing PD-1 in hepatocellular carcinoma lesions and their correlation with outcome suggest that immunotherapeutic approaches might be useful in this setting.12, 13, 14, 15

Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that disrupts PD-1 immune checkpoint signalling and thereby restores the antitumour activity of otherwise suppressed effector T cells. CheckMate 040 is an ongoing, global, phase 1/2 study of nivolumab in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis who were previously treated or untreated with sorafenib. In this first report of a PD-1 checkpoint inhibitor for the treatment of advanced hepatocellular carcinoma, we detail nivolumab safety and efficacy results from the dose-escalation and dose-expansion phases of CheckMate 040.

Section snippets

Study design and participants

We did a multicentre, non-comparative, open-label, phase 1/2 study in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis (HCV or HBV) to evaluate the safety and efficacy of nivolumab as a monotherapy (CheckMate 040). The dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and the dose-expansion phase was conducted at 39 sites in 11 countries (Canada, UK, Germany,

Results

The cutoff date for this analysis was Aug 8, 2016. Between Nov 26, 2012, and Aug 8, 2016, 262 patients with advanced hepatocellular carcinoma with or without HCV or HBV infection were treated: 48 patients in the dose-escalation phase and 214 in the dose-expansion phase (figure 1). Intravenous nivolumab monotherapy doses were 0·1–10 mg/kg every 2 weeks in the dose-escalation phase, and cohorts included 23 patients without viral hepatitis, ten patients with HCV infection, and 15 patients with HBV

Discussion

Previous studies6, 7, 19 in advanced hepatocellular carcinoma of first-line sorafenib have shown response rates of 2–3% and second-line regorafenib has shown a response rate of 7%. In this phase 1/2 study, treatment with nivolumab resulted in substantial tumour reductions and objective response rates of 15–20% irrespective of line of therapy in patients with advanced hepatocellular carcinoma. Notably, the disease control rate was 58% in the dose-escalation phase and 64% in the dose-expansion

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