a PD-1 checkpoint inhibitor that helps the immune system fight cancer, was associated
with a decrease in tumour size or disease stabilisation in people with
hepatocellular carcinoma (HCC) in the CheckMate 040 study, according to a
report at the 2017 AASLD Liver Meeting last month in Washington, DC.
Over years or decades, chronic hepatitis B or C virus
(HBV or HCV) infection, heavy alcohol use, fatty liver or other causes of liver
damage can lead to cirrhosis and HCC, a type of primary liver cancer. People
with hepatitis C who have progressed to cirrhosis remain at risk for liver cancer even after being cured
with effective antiviral therapy. HCC is often diagnosed late, when it is
difficult to treat, and it is a leading cause of cancer-related death
The kinase inhibitor sorafenib (Nexavar) is the only approved first-line therapy for HCC that
cannot be surgically removed, but it typically extends survival by only a few
months. The US Food and Drug Administration recently approved nivolumab for second-line therapy
after sorafenib. Nivolumab is currently approved in Europe
for advanced lung, kidney, bladder and head and neck cancers and Hodgkin
lymphoma, but not yet for liver cancer.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
type of tumour affecting the lymph nodes.
Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.
Bruno Sangro of Clinica Universidad de Navarra in
Pamplona, Spain, presented findings from Bristol-Myers Squibb's CheckMate 040
trial, which evaluated different doses of nivolumab in people with advanced
HCC, including those with chronic hepatitis B or C.
Nivolumab is a monoclonal antibody that blocks the PD-1 (programmed death) receptor on T-cells. PD-1
regulates immune response by suppressing excessive immune activation. Some
tumours can use PD-1 to turn off immune responses, and drugs that block PD-1 or
its ligand PD-L1 can restore T-cell activity against cancer cells.
CheckMate 040 included a phase 1 dose escalation cohort
in which 48 participants received intravenous infusions of nivolumab at doses
of 0.1 to 10.0 mg/kg every two weeks. After the 3.0 mg/kg dose was selected,
214 more people were enrolled in a phase 2 dose expansion cohort. There was no placebo or comparator drug arm.
In the dose escalation and expansion cohorts together,
about 80% of participants were men, half were white, 45% were Asian and the median
age was 63 years. A quarter had hepatitis B (and had to be on suppressive
antiviral therapy), another quarter had hepatitis C and half were not infected
with either virus.
Participants had biopsy-confirmed advanced HCC not
amenable to curative surgery. More than 70 per cent had metastases, or cancer spread beyond the liver.
About two-thirds had previously used sorafenib, and most of those had disease
progression while taking it. The remainder were intolerant of or unwilling to
The primary study endpoints were
safety and objective response, meaning either complete or partial tumour
shrinkage. Secondary endpoints included disease control (meaning either tumour
shrinkage or stable disease), time to response, duration of response and
objective response rates were 20% for people who had never used sorafenib and
19% and 14%, respectively, for sorafenib-experienced people in the dose
escalation and expansion cohorts. Among people who could not take sorafenib due
to intolerance, the objective response rate was 23%, compared with 15% among
those who progressed while on sorafenib. Complete tumour regression was
uncommon in all groups (1 to 3%).
disease rates were 31% in the sorafenib-naive group and 32% and 41%,
respectively, in the two sorafenib-experienced groups. Combining objective
response and stable disease rates, 54% of people who had never used sorafenib
and 55% of those who had done so did not experience disease progression.
The median overall survival was 15.0 and 15.6 months in the two
sorafenib-experienced groups. In comparison, people who switched from sorafenib
to a recently approved similar drug, regorafenib (Stivarga), had a median survival of about 11 months. The median
survival for the sorafenib-naive group could not be determined because a
majority of people were still alive, but this was projected to be 28.6 months.
noted that nearly 40% of participants with hepatitis C had at least a 1 log10
drop in HCV RNA after starting nivolumab, and one person was cured without
taking hepatitis C therapy. Nivolumab had no consistent effect on HBV levels.
Treatment with nivolumab was generally safe and well tolerated,
with no unexpected
side-effects not seen in other trials. The most common treatment-related
adverse events were fatigue, itching, rash and diarrhoea, which were mostly
mild or moderate and occurred with similar frequency in the sorafenib-naive and
biggest concern with PD-1 inhibitors is that they may unleash the immune system
too broadly, leading to excessive inflammation of healthy tissue. Some study
participants developed liver enzyme elevations suggestive of liver inflammation
(which the researchers said were easily managed) and one person died due to lung
Based on these findings,
the researchers concluded, "nivolumab demonstrated clinically meaningful
efficacy across etiologies in sorafenib-naive and -experienced patients with