Nivolumab
(Opdivo), 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 worldwide.
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.
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 take sorafenib.
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 overall survival.
The 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%).
Stable 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 participants were still alive, but
this was projected to be 28.6 months.
Sangro
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 -experienced groups.
The 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 inflammation (pneumonitis).
Based on these findings, the researchers concluded,
"nivolumab demonstrated clinically meaningful efficacy across etiologies
in sorafenib-naive and -experienced patients with extended follow-up."