Immunotherapy combinations show promise for liver cancer

Checkpoint inhibitor immunotherapy combinations may slow disease progression in people with hepatocellular carcinoma (HCC), according to two small studies presented at the 2019 Gastrointestinal Cancers Symposium last month in San Francisco. However, response rates remain low for this difficult-to-treat cancer.

For people with inoperable advanced liver cancer or biliary tract cancer, one study suggested that a regimen of durvalumab (Imfinzi) plus tremelimumab (not yet approved) may delay disease progression. For those with less advanced HCC, pre-surgery treatment with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) shrank tumours in a third of people.

Over years or decades, chronic hepatitis B or C, heavy alcohol use, fatty liver disease or other causes of liver damage can lead to cirrhosis and HCC, the most common type of primary liver cancer. Often diagnosed at a late stage, liver cancer is hard to treat and is a leading cause of cancer deaths worldwide. HCC does not respond well to traditional chemotherapy and a majority of people do not respond to current targeted therapies or immunotherapies. Biliary tract cancer, involving the gallbladder or bile ducts, is even more difficult to treat.

Nivolumab is a monoclonal antibody that blocks the PD-1 receptor on T-cells, an immune checkpoint that helps regulate immune function; durvalumab blocks its binding partner, known as PD-L1. Some tumours can use PD-1 to turn off immune responses against them. Drugs that block the interaction between PD-1 and PD-L1 can release the brakes and restore T-cell activity. Ipilimumab and tremelimumab block CTLA-4, a different immune checkpoint that suppresses T-cell multiplication.

Charalampos Floudas and colleagues from the US National Cancer Institute evaluated a combination of durvalumab and tremelimumab in 10 people with HCC and 12 with biliary tract cancers that could not be surgically removed or treated locally.

A majority of participants were men and the median age was 63 years. Seven of the liver cancer patients had hepatitis C and one had hepatitis B; most had compensated liver disease. A quarter had cancer that had spread beyond the liver or biliary tract. They had previously tried (or been offered and refused) at least one prior therapy.

Participants were treated with durvalumab plus tremelimumab for four monthly cycles, followed by once-monthly durvalumab monotherapy until disease progression or unacceptable toxicity. CT scans were performed every eight weeks to monitor disease progression.

Two people with liver cancer (20%) and one person with biliary tract cancer (8.3%) achieved partial responses; there were no complete responses. Five people with HCC (50%) and five people with biliary tract cancer (41.7%) had stable disease, meaning they neither improved nor worsened. Adding these numbers together, the disease control rate was 70% for HCC and 50% for biliary tract cancer.

In the liver cancer group, the median progression-free survival, meaning patients were still alive without worsening of disease, was 7.8 months and the median overall survival was 15.9 months. The biliary tract cancer group fared worse, with a median progression-free survival of 3.1 months and a median overall survival of 5.45 months.

These findings for the people with HCC compare favourably to the response rate of around 20%, stable disease rate of around 35% and median overall survival of about 15 months for previously treated people in the CheckMate 040 study of nivolumab for HCC. In that study, survival was substantially longer for treatment-naive patients. Overall survival has generally been shorter in studies of targeted therapies such as sorafenib (Nexavar) or lenvatinib (Lenvima).

"Combined immune checkpoint inhibition with Imfinzi and tremelimumab "is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC," the researchers concluded.

This study did not include a comparison group taking durvalumab alone, so it is unclear how much tremelimumab contributed to efficacy. This question will be addressed in the phase 3 HIMALAYA trial, in which people with liver cancer will be randomised to receive durvalumab alone, sorafenib alone or one of two regimens combining durvalumab and tremelimumab.

CheckMate 040 showed that nivolumab monotherapy delays disease progression or death in people with advanced HCC that cannot be cured with surgery. But what about those with less advanced liver cancer?

If diagnosed early, liver tumours can sometimes be surgically removed (known as resection), but the recurrence rate is high. In other types of cancer, neoadjuvant therapy is used to shrink tumours prior to surgery, whilst adjuvant therapy is used to reduce the risk of post-surgery relapse.

Ahmed Kaseb and colleagues from MD Anderson Cancer Center in Houston conducted a phase 2 pilot study to evaluate whether nivolumab alone or with ipilimumab might work as neoadjuvant therapy in people with HCC eligible for surgical resection.

The first interim analysis included eight evaluable patients. A majority were men and most were in their sixties. Five had hepatitis C and two had hepatitis B. Five received nivolumab monotherapy and three received nivolumab plus ipilimumab. Nivolumab was given every two weeks for a total of six weeks and ipilimumab was given on the first day. The participants underwent surgery at week six and will continue post-surgery immunotherapy for up to two years.

All eight participants proceeded to surgery as planned, but one was unable to complete the operation. Three of the eight people (37.5%) – two taking nivolumab alone and one taking the combination – experienced pathological complete response, meaning no evidence of cancer in the liver tissue removed during surgery.

Treatment was safe and generally well tolerated and did not lead to delays in surgery. One person experienced severe side-effects before surgery and two did so during post-operative follow-up.

Although the results are still preliminary, the researchers suggested that their findings "may contribute to a paradigm shift in the perioperative treatment of resectable HCC."