combination of nivolumab (Opdivo) and
ipilimumab (Yervoy), two different
types of checkpoint inhibitor immunotherapy, led to higher response rates and
longer survival than nivolumab alone in people with advanced liver cancer, according
to a study presented at the AASLD Liver
Meeting this month in Boston.
A third of people treated with the
most effective combination regimen experienced tumour regression, the median
overall survival was nearly two years and side effects were generally
manageable, reported Dr Bruno Sangro of Clinica Universidad
de Navarra in Spain.
Over years or decades, chronic hepatitis B or C, heavy
alcohol use, fatty liver disease and other causes can lead to the development
of liver cirrhosis and hepatocellular carcinoma (HCC), the most common type of
liver cancer. HCC, which is often detected late, is difficult to treat and
typically does not respond well to traditional chemotherapy.
of the bowels.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.
Partial recovery from an illness, an alternative word for regression.
Nivolumab is a PD-1
checkpoint inhibitor that helps the immune system fight cancer. PD-1
is a receptor on T-cells that helps regulate immune function. Drugs that block
the interaction between PD-1 and its binding partner, PD-L1, can restore T-cell
activity against tumours. Ipilimumab is a different type of checkpoint
inhibitor that blocks the CTLA-4 receptor, which dampens immune responses by suppressing
Nivolumab was approved in the US in 2017 for people with
previously treated liver cancer, but Bristol-Myers Squibb withdrew its application for European approval.
Sangro presented the latest results
from the phase I/II CheckMate 040 trial, which
is evaluating nivolumab alone and in combination with other drugs in diverse
groups of patients with previously treated advanced HCC.
reported at the 2017 Liver Meeting, this study previously showed that nivolumab alone led to an overall
response rate – meaning complete or partial tumour shrinkage – of 14% to 19% and a
median overall survival duration of about 16 months in people previously
treated with sorafenib (Nexavar), the
standard targeted therapy for HCC.
trial subsequently evaluated nivolumab in combination with ipilimumab. This
analysis included 148 people with advanced HCC who had previously taken or
could not tolerate sorafenib. About 80% were men, two-thirds were Asian, a
third were white and the median age was 60 years. About half had hepatitis B
and 22% had hepatitis C. In most cases, the cancer had spread beyond the liver.
About 20% had PD-L1 levels of 1% or higher, a factor that has been found to
predict better response to nivolumab in some studies.
were randomised to receive one of three different dosing regimens of nivolumab
plus ipilimumab, continuing until they experienced disease progression or
- Arm A: 1mg/kg nivolumab + 3 mg/kg ipilimumab every
three weeks for four cycles, followed by 240mg nivolumab every
Arm B: 3 mg/kg nivolumab + 1 mg/kg ipilimumab every
three weeks for four cycles, followed by 240mg nivolumab every two weeks
Arm C: 3 mg/kg nivolumab every two weeks + 1 mg/kg
ipilimumab every six weeks.
The regimen used in Arm A was most effective. Although
overall response rates were similar in Arms A, B and C (32%, 31% and 31%,
respectively), the complete response rate, meaning full tumour remission, was
highest in Arm A, at 8%, Dr Sangro reported.
The median overall survival was about twice as long in
Arm A compared with Arms B and C (22.8, 12.5 and 12.7 months, respectively). Overall
survival rates at 12 months were 61%, 56% and 51%, respectively, in the three
arms. At 24 months, the corresponding rates were 48%, 30% and 42%.
Response rates in Arm A were similar for people with
hepatitis B, hepatitis C or neither virus (32%, 29% and 31%, respectively). The
median survival duration appeared longer for those with hepatitis B or neither
virus compared to those with hepatitis C (22.2, 22.8 and 14.9 months, respectively),
though the numbers in each group were small and this difference could have been
due to chance.
In Arms A and B, overall response rates were similar regardless
of whether patients had a PD-L1 level above or below 1%. In Arm C, however, the
response rate rose to 50% for those with PD-L1 expression of 1% or higher.
Although the combination was generally safe, severe
(grade 3-4) adverse events were common (53%, 29% and 31%, respectively, in the
three arms). As checkpoint inhibitors restore immune
responses against cancer, they can also activate the immune system more broadly,
causing T-cells to attack the body. Immune-mediated adverse events were more
frequently reported in Arm A than in the other two arms. In that group, the
most common severe adverse event of this type was liver inflammation (20%),
followed by skin rash, endocrine problems, lung inflammation and colitis (all
6% or less).
Most treatment-related adverse events
were manageable and reversible, and most of those with
severe immune-mediated adverse events were successfully treated with a short
course of corticosteroids, Dr Sangro reported.
Dr Sangro said that a new phase III
clinical trial, CheckMate 9DW,
will evaluate nivolumab plus ipilimumab versus the targeted therapies sorafenib
or lenvatinib (Lenvima) as first-line
treatment for advanced HCC.
As reported at the recent European
Society for Medical Oncology Congress, the CheckMate-459 trial previously found
that nivolumab alone did not reach the statistical threshold for improved
overall survival compared with sorafenib, though it did double the overall
response rate and appeared to be better tolerated. The new study will evaluate
whether adding ipilimumab could improve response rates and prolong survival.
alone and in combination with ipilimumab is also being evaluated as neoadjuvant
therapy for people with less advanced HCC. This type of treatment aims to
shrink tumours enough to enable them to be surgically removed. An analysis of
eight patients earlier last year showed that three people – two taking
nivolumab alone and one taking the combination – experienced pathological
complete response, meaning no evidence of cancer remaining in the liver tissue
removed during surgery.