Elsevier

The Lancet Oncology

Volume 19, Issue 7, July 2018, Pages 940-952
The Lancet Oncology

Articles
Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial

https://doi.org/10.1016/S1470-2045(18)30351-6Get rights and content

Summary

Background

Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population.

Methods

KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414.

Findings

Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares.

Interpretation

Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma.

Funding

Merck & Co, Inc.

Introduction

Hepatocellular carcinoma is one of the most common causes of cancer-related deaths worldwide. In most patients, hepatocellular carcinoma arises in conjunction with liver cirrhosis and is attributed to several risk factors, including infection (usually with hepatitis B or C viruses), excessive alcohol consumption, and non-alcoholic fatty liver disease.1, 2 Surgical resection, transplantation, and ablation are potentially curative treatment options for patients with early-stage disease; however, most patients present with advanced, unresectable disease.1 These patients are typically treated worldwide with locoregional and systemic therapies.

Sorafenib, a multi-kinase inhibitor, remains the standard first-line systemic treatment for advanced hepatocellular carcinoma, and lenvatinib has been shown to be non-inferior to sorafenib in overall survival3, 4, 5 and is approved for treatment in Japan. All other treatments that have been assessed as first-line therapy, and several other drugs that have been evaluated as second-line therapies have not shown improved survival over sorafenib or placebo.6 Regorafenib, another anti-angiogenic multi-kinase inhibitor, is the only second-line therapy that has been globally approved for use after treatment with sorafenib in patients with hepatocellular carcinoma.7 In 2018, cabozantinib was shown to improve overall survival compared with placebo in patients with advanced hepatocellular carcinoma who were intolerant to or had progressive disease after sorafenib treatment.8 A phase 3 study9 (REACH-2) that evaluated ramucirumab as a second-line therapy in patients with hepatocellular carcinoma who had blood concentrations of alpha-fetoprotein of at least 400 ng/mL also showed improved overall survival compared with placebo. Although these inhibitors have led to improved survival, the benefits remain modest and many of these drugs have prohibitive side-effects. Novel treatment strategies for these patients are desperately needed.

Research in context

Evidence before this study

Few treatment options are available for patients with advanced hepatocellular carcinoma. First-line sorafenib and second-line regorafenib therapies have been approved; however, these treatments have modest efficacy and associated toxicity. Thus, there is an unmet need to develop additional therapeutic strategies and identify biomarkers that are predictive of therapeutic response in these patients. Immunotherapies, including checkpoint blockade therapies, have shown promising preliminary results in patients with hepatocellular carcinoma, and the programmed cell death protein-1 (PD-1) inhibitor nivolumab has received accelerated approval for second-line treatment in the USA. We searched PubMed from Sept 1, 2017, to Feb 22, 2018, with the search terms “advanced hepatocellular carcinoma AND treatment”, “immunotherapy AND hepatocellular carcinoma”, “anti-PD-1 OR pembrolizumab OR MK-3475 OR nivolumab AND hepatocellular carcinoma”, and “biomarkers AND immunotherapy AND hepatocellular carcinoma”. This search was limited to articles and abstracts in English. We found few studies that evaluated immunotherapy in hepatocellular carcinoma; in one study, the cytotoxic T lymphocyte antigen inhibitor, tremelimumab, showed antitumour activity and manageable toxicity in patients with advanced hepatocellular carcinoma. Combination therapy with the programmed death-ligand 1 (PD-L1) inhibitor durvalumab and tremelimumab also showed encouraging preliminary results and no unexpected safety signals in patients with hepatocellular carcinoma. The only study that has described treatment of patients with hepatocellular carcinoma with an anti-PD-1 inhibitor was that of nivolumab, which showed promising outcomes and a safety profile generally consistent with that reported for nivolumab in other tumour types. Apart from the nivolumab study, which suggested that PD-L1 expression in tumour cells was not significantly associated with a clinical response, no relevant studies have evaluated biomarkers of response to immunotherapy in hepatocellular carcinoma, as was done in our study.

Added value of this study

To our knowledge, the KEYNOTE-224 study is the first to show the clinical efficacy and safety of pembrolizumab in patients with advanced hepatocellular carcinoma who were previously treated with sorafenib. A substantial proportion of patients had objective responses and both median progression-free survival and overall survival were promising after treatment with pembrolizumab. These results are also consistent with findings for nivolumab in these patients, indicating the importance of anti-PD-1 therapy as a potential treatment option for these patients. The study also showed that PD-L1 expression, as shown by combined positive score (a measure of PD-L1-positive immune and tumour cell number), was associated with response to pembrolizumab; however, further study is needed to determine the clinical usefulness of PD-L1 in predicting response to anti-PD-1 therapy in patients with advanced hepatocellular carcinoma.

Implications of all the available evidence

Overall, this study indicated that pembrolizumab could be an additional treatment option for patients with advanced hepatocellular carcinoma whose disease progressed on or were intolerant to previous sorafenib therapy; further assessment is ongoing in the phase 3 KEYNOTE-240 and KEYNOTE-394 trials in patients with second-line advanced hepatocellular carcinoma. PD-L1 expression, as assessed by the combined positive score, appeared to be associated with response to pembrolizumab in these patients; however, additional studies are needed to better understand the associations between biomarkers and response to anti-PD-1 therapy in hepatocellular carcinoma.

The liver maintains a balance between activation of and tolerance by immune cells in response to antigenic hyperstimulation, and dysregulation of this tightly controlled immunological network leads to chronic liver disease and hepatocellular carcinoma.2 Hepatocellular carcinoma has been shown to be associated with inflammation and a suppressed immune environment.2, 10 An inflammatory gene-expression signature was shown to be predictive of lower overall survival in liver tissue adjacent to tumours in patients with hepatocellular carcinoma,11 and high expression of programmed death-ligand 1 (PD-L1) in tumours correlates with a poorer prognosis than lower expression of PD-L1 in patients with resected hepatocellular carcinoma.12 Upregulation of programmed cell death protein-1 (PD-1) and PD-L1 expression on T cells is also associated with a more advanced disease stage and higher recurrence rates in patients with hepatocellular carcinoma.13 Signature genes in subsets of infiltrating regulatory T cells and exhausted CD8+ cells of patients with hepatocellular carcinoma have been identified, including layillin (LAYN), which might be linked to immune suppression by these cells.14 These immunological findings suggest that immunotherapy approaches could benefit these patients.

Immunotherapy with checkpoint blockade inhibitors has shown promising preliminary results in patients with advanced hepatocellular carcinoma, either as monotherapy or combination therapy.2 The anti-PD-1 inhibitor nivolumab has shown encouraging outcomes and a safety profile that is generally consistent with that reported in other tumour types and, as such, has received accelerated approval in the USA for the treatment of hepatocellular carcinoma that has previously been treated with sorafenib.15, 16 Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown antitumour activity and a manageable safety profile in several cancers, including melanoma, non-small cell lung cancer, head and neck cancer, squamous cell carcinoma, gastric and urothelial cancers, and classical Hodgkin's lymphoma.17, 18

We present the results of KEYNOTE-224, an open-label, phase 2 trial, in which we aim to evaluate the efficacy and safety of pembrolizumab in patients with advanced hepatocellular carcinoma who have been previously treated with sorafenib, and to assess the association between PD-L1 expression and clinical outcomes.

Section snippets

Study design and participants

KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial of pembrolizumab in patients with advanced hepatocellular carcinoma who have previously been treated with sorafenib. The trial was done at 47 medical centres and hospitals in ten countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, Sweden, the UK, and the USA; appendix p 2); participants were enrolled at 38 sites (appendix p 3).

Patients who were eligible for the trial were aged at least 18 years; had a

Results

Between June 7, 2016, and Feb 9, 2017, 169 patients were assessed for eligibility. Of these patients, 64 (38%) were deemed ineligible because they did not meet the inclusion criteria or met exclusion criteria (figure 1). We enrolled participants between June 22, 2016, and Feb 20, 2017. One (1%) patient was enrolled in error. 104 enrolled patients were treated with at least one dose of pembrolizumab and were included in the primary analysis. The baseline characteristics of the enrolled

Discussion

In this phase 2 trial, pembolizumab showed promising clinical efficacy and manageable safety in patients with advanced hepatocellular carcinoma who were previously treated with sorafenib. To our knowledge, this trial was the first to evaluate pembrolizumab in this patient population. We found a substantial number of objective responses (17%) that were consistently observed across several risk factors associated with the prognosis of hepatocellular carcinoma, including hepatitis B virus and

References (33)

  • M Kudo

    Systemic therapy for hepatocellular carcinoma: 2017 update

    Oncology

    (2017)
  • GK Abou-Alfa et al.

    Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial

    Proc Am Soc Clin Oncol

    (2018)
  • Lilly announces CYRAMZA (ramucirumab) phase 3 REACH-2 Study in second-line hepatocellular carcinoma patients met overall survival endpoint

  • J Prieto et al.

    Immunological landscape and immunotherapy of hepatocellular carcinoma

    Nat Rev Gastroenterol Hepatol

    (2015)
  • Y Hoshida et al.

    Gene expression in fixed tissues and outcome in hepatocellular carcinoma

    N Engl J Med

    (2008)
  • Q Gao et al.

    Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma

    Clin Cancer Res

    (2009)
  • Cited by (1799)

    View all citing articles on Scopus

    Investigators listed in the appendix, p2

    View full text