Bristol-Myers Squibb's PD-1 immune checkpoint
inhibitor nivolumab (Opdivo)
demonstrated good safety and anti-tumour activity against hepatocellular
carcinoma in a phase 1/2 study presented at the American Society of Clinical
Oncology (ASCO) annual meeting this week in Chicago, USA. Phase 3 data showing the
drug's effectiveness against lung cancer and melanoma were also reported at the
conference.
Over years or decades, chronic hepatitis B or C virus
(HBV or HCV) infection, heavy alcohol use and other factors can lead to
advanced liver disease including cirrhosis (accumulation of scar tissue) and
hepatocellular carcinoma (HCC), a type of liver cancer.
HCC is often diagnosed late, remains difficult to
treat and is a leading cause of cancer death worldwide. The tyrosine kinase
inhibitor sorafenib (Nexavar) is
currently the only approved drug for liver cancer that cannot be surgically
removed, but it typically only extends survival by a few months and more
effective therapies are needed.
Glossary
- amylase
An enzyme produced in the pancreas and saliva which assists in the digestion of starch.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
Anthony El-Khoueiry of the Norris Comprehensive Cancer
Centre at the University of Southern California and colleagues
evaluated nivolumab for people with advanced hepatocellular carcinoma in a phase
1/2 trial (NCT01658878).
Nivolumab is a human monoclonal antibody that targets
PD-1 (programmed death protein 1),
a cell signalling molecule
expressed on immune cells. PD-1 plays a role in regulating immune response by
dampening excessive immune activation. By blocking PD-1 or its ligand (binding
partner) PD-L1, checkpoint inhibitors like nivolumab can release or re-enable
immune responses against cancerous cells. Prior research has shown that HCC
tumours that express high levels of PD-L1 have poor prognosis.
This multiple ascending dose trial enrolled 47
participants with histologically
confirmed advanced HCC, of whom 11 had active hepatitis B and 12 had hepatitis
C. They had progressive disease with Child-Pugh class B scores of 5 or 6
(indicating relatively good liver function) and ECOG scores
of 0 (asymptomatic) or 1 (some symptoms but fully ambulatory). Eighty per cent had portal
vein tumour invasion or metastasis beyond the liver. About 75% had previously been treated for
HCC, including 68% with sorafenib.
All participants were
treated with intravenous infusions of nivolumab at doses of 0.1 to 10.0mg/kg
every other week for up to two years; there was no comparator drug or placebo
in this early clinical trial. The primary endpoint was safety, with a secondary
endpoint of anti-tumour activity.
At the time of this
interim analysis, 17 study participants remained on treatment, while the rest had discontinued
therapy due to disease progression (26 people), adverse events (two with
drug-related events) or complete response.
Among the 42
participants who could be evaluated for efficacy, eight (19%) showed anti-tumour
responses with tumour reduction of at least 30%. Two of these participants (5%)
experienced complete responses while six (14%) had partial responses (a
reduction in tumour size of between 30 and 100%). The overall survival rate
was 62% at 12 months.
Treatment with
nivolumab was generally safe and well-tolerated. Thirty-two participants (68%)
experienced any drug-related adverse events, including 19% with grade 3/4
events. Adverse events reported by at least 15% of participants included skin rash
(17%) and ALT, AST, lipase and amylase elevations. There was no evidence of liver flares or worsening of HBV or HCV infection.
"Nivolumab monotherapy has a manageable safety profile
in patients with HCC, including those with HBV or HCV infection," and
"durable responses were observed across all dose levels and etiologic
cohorts," the researchers concluded. "Encouraging 12-month overall
survival was observed."
The response rates with
nivolumab in this study compare favourably with a complete response rate of
around 2% and a one-year overall survival rate of about 30% with sorafenib.
"These preliminary data are encouraging and
support the on-going evaluation of nivolumab in this patient population, as
they show promising preliminary survival data, and durable partial or complete
response in 1 out of 5 nivolumab-treated patients, with many others
experiencing stable disease," El-Khoueiry stated in a Bristol-Myers Squibb
press release.
Commenting on the study findings,
Lawrence Fong of the University of California at San Francisco said, "For
this disease with limited treatment options, nivolumab shows that patients can
achieve a durable response." He added that the study allays concerns that
immune checkpoint inhibitors may not be safe for people with viral infections
such as HBV or HCV.