Nivolumab increases survival for people with advanced liver cancer

The checkpoint inhibitor nivolumab (Opdivo) produced durable responses, prolonged overall survival, and was generally well tolerated as a treatment for advanced liver cancer that did not respond to standard treatment, researchers reported on Friday at the International Liver Congress in Amsterdam. The congress is the annual meeting of the European Association for the Study of the Liver (EASL).

Over years or decades, chronic hepatitis B or C virus infection, heavy alcohol use or other causes of liver injury can lead to development of liver cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer. People with hepatitis C who have progressed to cirrhosis remain at risk for HCC even after being cured with antiviral therapy.

HCC is often diagnosed late and is difficult to treat. The only current treatment, the multikinase inhibitor sorafenib (Nexavar), does not work for many people with HCC, and a large majority experience disease progression. Several other therapy candidates have failed in clinical trials.

Nivolumab and other checkpoint inhibitors are important in the burgeoning field of immune oncology, which aims to enhance immune responses against cancer rather than attacking it with poorly tolerated therapies such as chemotherapy or radiation.

Nivolumab (Opdivo) is already licensed in the United States and the European Union for the treatment of several cancers that have not responded to previous treatment regimens and is now being tested in early phase trials as a treatment for hepatocellular carcinoma.

Nivolumab is a humanised monoclonal antibody that blocks the PD-1 (programmed death) protein expressed on T-cells. PD-1 triggers cell exhaustion as a way of curbing excessive immune response. Blocking this process can restore T-cell activity against tumour cells.

Jörg Trojan of Goethe University Hospital and Cancer Centre in Frankfurt presented findings from Bristol-Myers Squibb's phase 1/2 CheckMate 040 trial (NCT01658878), which evaluated nivolumab in people with advanced HCC who were not eligible for surgical resection. Bruno Sangro of Clinica Universidad de Navarra in Pamplona, Spain, gave an overview of the results at an EASL press conference.

The study enrolled a total of 262 patients. A small cohort first participated in a dose-escalation phase, testing intravenous infusions of nivolumab at doses ranging from 0.1 to 10 mg/kg. A 3 mg/kg dose given every two weeks was selected and additional patients were then added.

Drs Trojan and Sangro presented findings from a cohort of 145 treatment-experienced people who received the 3 mg/kg dose. There was no placebo or comparator drug arm. Most participants were men, with a median age of approximately 60 years. About 20% had hepatitis C, nearly 30% had hepatitis B and the rest were uninfected.

Participants had tried at least one previous systemic cancer therapy. Almost all had progressed on sorafenib and a majority had undergone prior surgical resection. More than half had metastases beyond the liver. However, they had generally well-preserved liver function with Child-Pugh scores of 5 or 6.

More than 60% of sorafenib-experienced patients showed some level of HCC disease control. Overall, 19% demonstrated an objective response to nivolumab as assessed by study investigators using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, while 44% had stable disease and 32% experienced disease progression.

Three people (2%) had a complete response and 25 (17%) had a partial response. Broken down by cause of HCC, objective response rates were 27% for hepatitis C, 14% for hepatitis B, and 19% for uninfected patients. Objective response occurred regardless of whether patients had high or low expression of PD-L1 – the ligand or binding partner of PD-1 – on their T-cells.

The median time to response ranged from two to four months, with 57% responding within three months. Responses to nivolumab were quite durable. By one criterion, the median duration of response was 12.4 months, but by another the median duration could not be determined because more than half of patients still showed ongoing response. A few people sustained responses through three years of follow-up, according to Sangro.

The median overall survival was 16.7 months – a notable improvement over the current standard of care for people with advanced liver cancer. The overall survival rate at 12 months was 60%, and was similar in hepatitis C, hepatitis B and uninfected patients.

Treatment with 3 mg/kg nivolumab was generally safe and well tolerated. Grade 3/4 adverse events were uncommon (17%). The most common treatment-related adverse events were fatigue (24%), itching (19%), rash (16%) and diarrhoea (14%). Side-effects were similar in the hepatitis C, hepatitis B and uninfected groups.

Nivolumab had a minimal effect on hepatitis C or hepatitis B viral load overall, though a small number of people did see substantial decreases.

"In patients with advanced HCC who were previously treated with sorafenib, nivolumab increased survival and demonstrated durable and sustainable response," Sangro summarised. "Responses were demonstrated across HCV-infected, HBV-infected, and uninfected patients."

"The safety profile of nivolumab was manageable, and no new safety signals were observed," he continued. "These results suggest nivolumab is a valuable treatment option for patients with HCC who progress on or are intolerant of sorafenib."

A randomised phase 3 study, CheckMate 459, is now underway comparing nivolumab versus sorafenib for first-line treatment of people with advanced HCC.