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.
Glossary
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
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.