Nivolumab (Opdivo),
a checkpoint inhibitor that helps the immune system fight cancer, was
associated with tumour shrinkage or disease stabilisation in just over half of hepatocellular
carcinoma (HCC) patients with substantial liver function impairment, according to a presentation at the AASLD Liver
Meeting this month in San Francisco.
Over years or decades, chronic hepatitis B or C virus
(HBV or HCV) infection, heavy alcohol use, fatty liver disease or other causes
of liver damage can lead to cirrhosis and HCC, a type of primary liver cancer. HCC
is often diagnosed at a late stage, is difficult to treat and is a leading
cause of cancer mortality worldwide.
Nivolumab is a monoclonal antibody that blocks the
PD-1 receptor on T-cells, an immune checkpoint
that plays a
role in regulating immune function. Some tumours can use
PD-1 to turn off immune responses against them. Drugs that block the
interaction between PD-1 and its ligand, known as PD-L1, can release the brakes
and restore T-cell activity.
The US
Food and Drug Administration approved nivolumab for liver cancer last year and another PD-1 checkpoint inhibitor,
pembrolizumab (Keytruda), earlier this month. The European Medicines Agency has
approved both drug for several types of cancer, but not yet for HCC.
Masatoshi
Kudo of Kindai University in Osaka reported the latest findings from the
CheckMate 040 trial, which is evaluating nivolumab as a treatment for people
with advanced HCC that cannot be surgically removed.
Researchers
previously reported primary results from this study, showing
an objective response rate (complete or partial tumour shrinkage) of around 20%
and a stable disease rate of around 30%. However, most participants in that analysis were classified as Child-Pugh class A,
meaning they had well-preserved liver function, or compensated liver disease.
This year Kudo presented data from a cohort of 49 trial participants classified as
Child-Pugh B, meaning more severely impaired liver function, with a higher risk
of liver failure and death.
A
majority of the Child-Pugh B participants were men and the median age was 67
years. About 43% had HCV, 16% had HBV and 41% had neither virus. They had stage
B or C liver disease according to the Barcelona (BCLC) system and 41% had
cancer metastasis beyond the liver. Half had previously used the kinase
inhibitor sorafenib (Nexavar), the
current first-line therapy for HCC that cannot be surgically removed.
All study participants received intravenous infusions
of nivolumab every two weeks until they experienced disease progression
or unacceptable side-effects.
After a median follow-up period of about 12 months, eight people (16%)
remained on treatment, 33 (67%) had stopped due to disease progression, two
(4%) did so because of nivolumab side-effects and three (6%) did so because of
unrelated adverse events.
The objective
response rate in this cohort was 10% – about half that observed for the
Child-Pugh A patients presented last year. There were no complete responses.
However, 45% of the Child-Pugh B patients had stable disease, slightly higher
than the 41% in the Child-Pugh A group. Taken together, this yielded a disease
control rate of 55% for the Child-Pugh B cohort, which did not differ greatly
from the 61% for the Child-Pugh A group.
Kudo
reported that a small number of Child-Pugh B patients had deep and durable responses,
including two with ongoing response. Four of the five best responders saw
their liver function improve enough to be reclassified as Child-Pugh A. The
median duration of response was 9.9 months.
The
median overall survival was 7.6 months, which Kudo noted is longer than
survival times seen in prior studies of Child-Pugh B patients treated with
sorafenib (around 2.5 to 5.0 months).
Despite their advanced liver disease, nivolumab was
generally safe and well tolerated by Child-Pugh B patients, with no unexpected side-effects and a
safety profile similar to that seen in the Child-Pugh A group. The most common
side-effects were rash, itching and gastrointestinal symptoms. One concern with
checkpoint inhibitors is that unleashing immune responses can lead to excessive
inflammation of healthy tissue. However, immune mediated reactions, including
worsening liver inflammation, were rare.
Based on these findings, the researchers concluded, "Nivolumab
showed promising efficacy and tolerability in patients with Child-Pugh B
status, supporting further investigation in this patient population."