an antibody that blocks the PD-1 receptor and restores T-cell anti-tumour
activity, appeared safe and was associated with disease control and
stabilisation in a phase 1/2 study of people with hepatocellular carcinoma,
according to late-breaking results from the CheckMate 040 study presented at
the 2016 AASLD Liver Meeting last November in Boston.
Hepatocellular carcinoma (HCC), a type of primary
liver cancer, can develop over years or decades in people with chronic
hepatitis B or C virus (HBV or HCV) infection, heavy alcohol use or other
causes of liver damage. People with hepatitis C who have progressed to liver
cirrhosis remain at risk for HCC even after being cured with effective antiviral
HCC is often diagnosed late when it is difficult to
treat, and it is a leading cause of cancer death worldwide. Sorafenib (Nexavar), a multikinase inhibitor, is
the standard of care for HCC that cannot be surgically removed or resected, but
it typically extends survival by only a few months and more effective therapies
are urgently needed.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
type of tumour affecting the lymph nodes.
Bruno Sangro of Clinica Universidad de Navarra in
Pamplona, Spain, presented findings from Bristol-Myers Squibb's CheckMate 040
trial, evaluating different doses of nivolumab in people with advanced HCC,
including those with chronic HBV or HCV infection.
Nivolumab is a human IgG4 monoclonal antibody that
blocks PD-1 (programmed death protein 1), a
cell-signalling molecule expressed on immune
cells. PD-1 regulates immune response by suppressing excessive immune
activation. By blocking the PD-1 receptor or its ligand (binding partner)
PD-L1, checkpoint inhibitors like nivolumab can re-enable immune responses
against tumour cells.
a brake on immune response, and nivolumab releases the brake," Sangro
Nivolumab is currently approved by the EMA
for treatment of advanced melanoma, non-small cell lung cancer and renal cell
carcinoma, and also for head and neck cancers and Hodgkin lymphoma in the US.
CheckMate 040 included a phase 1 dose escalation
segment that enrolled 48 participants and a phase 2 dose expansion segment that
enrolled 214 people. Individuals in the first part received ascending doses of
0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg nivolumab given by intravenous infusion every
two weeks. In the second part everyone received the selected 3.0 mg/kg dose.
There were no placebo or comparator drug arms in
this early trial.
Participants had biopsy-confirmed advanced HCC not
amenable to curative surgical resection. They had Child-Pugh scores < 7
(escalation) or < 6 (expansion), and AST and ALT liver enzyme levels < 5
times the upper limit of normal. They had experienced disease progression
despite prior treatment or were intolerant of or unwilling to take sorafenib.
Looking at the escalation and expansion cohorts
together, about 80% 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), 23% had hepatitis C and 51% did not have infection with either
virus; people with HBV/HCV co-infection were excluded.
Most participants (76%) had cancer metastases beyond
the liver. Prior treatment included surgical resection (61%); local treatment
such as transcatheter arterial chemoembolization, radiofrequency ablation or
percutaneous ethanol injection (60%); and radiation therapy (19%).
Three-quarters had received prior systemic therapy, mostly with sorafenib
The primary study endpoints were
safety and tolerability in the escalation segment and objective response
in the expansion segment. Secondary endpoints included time to response,
duration of response and overall survival. Preliminary results from the dose
escalation cohort were previously presented
at the 2015 American Society of Clinical Oncology
Overall, 68% of people experienced some level of HCC
In the escalation cohort, seven people (15%) had a
protocol-defined objective response, and this was seen at all dose levels. Two
people in the uninfected group and one in the HCV group achieved complete
response (6%); 8% experienced partial response, with this being more common in
the HCV group. Half had stable disease that neither improved nor worsened,
while nearly a third had progressive or worsening HCC.
In the expansion cohort, 35 people (16%) had an
objective response. Two people in the uninfected group achieved complete
response (1%), while 15% overall experienced partial response. Again, about
half (52%) had stable disease and 29% had progressive disease.
Responses usually occurred within the first three
months of treatment and the median duration of response in the escalation
cohort was 17 months. In the expansion cohort 30 people had ongoing responses
for up to about 10 months of follow-up.
Median overall survival was 14.3 months in the
escalation cohort. Survival rates were 66% at six and nine months, 59% at 12
months and 44% at 18 months. In the expansion cohort, survival was 83% at six
months and 71% at nine months, with the later time points not yet reached.
Responses did not differ significantly based on PD-L1
expression on tumour cells. Some people (20%) in the HCV group saw transient
vial load declines of > 1 log10, but no one achieved sustained
virological response. Likewise, a few people (5%) in the HBV group had a
decline in hepatitis B surface antigen (HBsAg) levels.
Treatment was generally safe and well tolerated. Most
people (83%) in the escalation cohort and 43% in the expansion cohort
discontinued study treatment due to disease progression. One person (2%) in the
escalation cohort and eight people (4%) in the expansion cohort stopped due to
treatment-related adverse events or toxicity. Overall, 19 participants (7%)
experienced treatment-related serious adverse events. The most common
treatment-related side-effects were fatigue (18%), pruritus (15%), skin rash
(14%), diarrhoea (9%) and nausea (6%).
Objective responses to nivolumab monotherapy in
people with HCC "occurred early and were durable irrespective of
infection status, were observed regardless of prior sorafenib treatment, and
occurred in patients irrespective of PD-L1 expression on tumour cells,"
the researchers concluded.
"The overall survival rate was encouraging
and notable disease stabilization was observed, including in some patients who
progressed on prior sorafenib therapy," they added. "The manageable
safety profile was similar to what has been observed in other tumour types
without any new safety signals."
"challenges the assumption that immune therapy cannot be effective for
patients with a high tumour burden," Sangro said.
A randomised phase 3 study, CheckMate 459, comparing
nivolumab versus sorafenib for first-line treatment of people with advanced HCC
is now enrolling.