infohep is no longer being updated. Visit for HIV and hepatitis news.

Immunotherapy combination improves liver cancer survival

Liz Highleyman
27 November 2019
Bruno Sangro at The Liver Meeting. Photo by Liz Highleyman.

A combination of nivolumab (Opdivo) and ipilimumab (Yervoy), two different types of checkpoint inhibitor immunotherapy, led to higher response rates and longer survival than nivolumab alone in people with advanced liver cancer, according to a study presented at the AASLD Liver Meeting this month in Boston.

A third of people treated with the most effective combination regimen experienced tumour regression, the median overall survival was nearly two years and side effects were generally manageable, reported Dr Bruno Sangro of Clinica Universidad de Navarra in Spain.

Over years or decades, chronic hepatitis B or C, heavy alcohol use, fatty liver disease and other causes can lead to the development of liver cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer. HCC, which is often detected late, is difficult to treat and typically does not respond well to traditional chemotherapy.



Inflammation of the bowels.

hepatocellular carcinoma (HCC)

Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.


Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.


Partial recovery from an illness, an alternative word for regression.

Nivolumab is a PD-1 checkpoint inhibitor that helps the immune system fight cancer. PD-1 is a receptor on T-cells that helps regulate immune function. Drugs that block the interaction between PD-1 and its binding partner, PD-L1, can restore T-cell activity against tumours. Ipilimumab is a different type of checkpoint inhibitor that blocks the CTLA-4 receptor, which dampens immune responses by suppressing T-cell replication.

Nivolumab was approved in the US in 2017 for people with previously treated liver cancer, but Bristol-Myers Squibb withdrew its application for European approval.

Sangro presented the latest results from the phase I/II CheckMate 040 trial, which is evaluating nivolumab alone and in combination with other drugs in diverse groups of patients with previously treated advanced HCC.

As reported at the 2017 Liver Meeting, this study previously showed that nivolumab alone led to an overall response rate – meaning complete or partial tumour shrinkage – of 14% to 19% and a median overall survival duration of about 16 months in people previously treated with sorafenib (Nexavar), the standard targeted therapy for HCC.

The trial subsequently evaluated nivolumab in combination with ipilimumab. This analysis included 148 people with advanced HCC who had previously taken or could not tolerate sorafenib. About 80% were men, two-thirds were Asian, a third were white and the median age was 60 years. About half had hepatitis B and 22% had hepatitis C. In most cases, the cancer had spread beyond the liver. About 20% had PD-L1 levels of 1% or higher, a factor that has been found to predict better response to nivolumab in some studies.

Participants were randomised to receive one of three different dosing regimens of nivolumab plus ipilimumab, continuing until they experienced disease progression or unacceptable toxicity:

  • Arm A: 1mg/kg nivolumab + 3 mg/kg ipilimumab every three weeks for four cycles, followed by 240mg nivolumab every two weeks
  • Arm B: 3 mg/kg nivolumab + 1 mg/kg ipilimumab every three weeks for four cycles, followed by 240mg nivolumab every two weeks
  • Arm C: 3 mg/kg nivolumab every two weeks + 1 mg/kg ipilimumab every six weeks.

The regimen used in Arm A was most effective. Although overall response rates were similar in Arms A, B and C (32%, 31% and 31%, respectively), the complete response rate, meaning full tumour remission, was highest in Arm A, at 8%, Dr Sangro reported.

The median overall survival was about twice as long in Arm A compared with Arms B and C (22.8, 12.5 and 12.7 months, respectively). Overall survival rates at 12 months were 61%, 56% and 51%, respectively, in the three arms. At 24 months, the corresponding rates were 48%, 30% and 42%.

Response rates in Arm A were similar for people with hepatitis B, hepatitis C or neither virus (32%, 29% and 31%, respectively). The median survival duration appeared longer for those with hepatitis B or neither virus compared to those with hepatitis C (22.2, 22.8 and 14.9 months, respectively), though the numbers in each group were small and this difference could have been due to chance.

In Arms A and B, overall response rates were similar regardless of whether patients had a PD-L1 level above or below 1%. In Arm C, however, the response rate rose to 50% for those with PD-L1 expression of 1% or higher.

Although the combination was generally safe, severe (grade 3-4) adverse events were common (53%, 29% and 31%, respectively, in the three arms). As checkpoint inhibitors restore immune responses against cancer, they can also activate the immune system more broadly, causing T-cells to attack the body. Immune-mediated adverse events were more frequently reported in Arm A than in the other two arms. In that group, the most common severe adverse event of this type was liver inflammation (20%), followed by skin rash, endocrine problems, lung inflammation and colitis (all 6% or less).

Most treatment-related adverse events were manageable and reversible, and most of those with severe immune-mediated adverse events were successfully treated with a short course of corticosteroids, Dr Sangro reported.

Dr Sangro said that a new phase III clinical trial, CheckMate 9DW, will evaluate nivolumab plus ipilimumab versus the targeted therapies sorafenib or lenvatinib (Lenvima) as first-line treatment for advanced HCC.

As reported at the recent European Society for Medical Oncology Congress, the CheckMate-459 trial previously found that nivolumab alone did not reach the statistical threshold for improved overall survival compared with sorafenib, though it did double the overall response rate and appeared to be better tolerated. The new study will evaluate whether adding ipilimumab could improve response rates and prolong survival.

Nivolumab alone and in combination with ipilimumab is also being evaluated as neoadjuvant therapy for people with less advanced HCC. This type of treatment aims to shrink tumours enough to enable them to be surgically removed. An analysis of eight patients earlier last year showed that three people – two taking nivolumab alone and one taking the combination – experienced pathological complete response, meaning no evidence of cancer remaining in the liver tissue removed during surgery.


Sangro B et al. CheckMate 040: efficacy, hepatic safety, and biomarkers of nivolumab + ipilimumab combination therapy in patients with advanced hepatocellular carcinoma. AASLD Liver Meeting, Boston, abstract 200, 2019. Hepatology 70:131A, 2019.