US FDA approves nivolumab immunotherapy for liver cancer

The US Food and Drug Administration (FDA) last week granted accelerated approval for nivolumab (Opdivo), an immunotherapy drug that restores T-cell anti-tumour activity, for people with hepatocellular carcinoma.

Nivolumab, an antibody that blocks the PD-1 (programmed death protein 1) receptor, was approved for people previously treated with sorafenib (Nexavar). Approval was supported by findings from the CheckMate 040 study presented at the 2016 AASLD Liver Meeting. While response rates in this study were not particularly high, there are few good existing options for people with this type of cancer, especially those with recurring disease.

Over years or decades chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, heavy alcohol use, fatty liver disease and other causes of liver injury can lead to serious liver disease including cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer. People with hepatitis B can develop HCC despite antiviral therapy, and people with hepatitis C who have progressed to cirrhosis remain at risk for liver cancer even after being cured with direct-acting antiviral therapy.


pharmacodynamics (PD)

The biochemical and physiological effects of drugs and their mechanisms of action in the body.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

European Medicines Agency (EMA)

Regulatory agency that evaluates medicines for safety and efficacy in Europe, performing a similar role to the Food and Drug Administration (FDA) in the United States. The EMA recommends to the European Commission that a medicine can be marketed in the European Union and European Economic Area.


Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

HCC is often diagnosed late and is difficult to treat, making it a leading cause of cancer death worldwide. Sorafenib, a tyrosine kinase inhibitor, is the standard of care for HCC that cannot be surgically removed, but it typically extends survival by only a few months. A similar drug, regorafenib (Stivarga), was recently approved for second-line HCC treatment, but there is an unmet need for more effective and longer-acting options.

Nivolumab is a human monoclonal antibody that interferes with PD-1, a cell-signalling molecule on T-cells. PD-1 regulates immune responses by suppressing excessive immune activation. Some cancers can hijack PD-1 to disable immune responses against them. By blocking PD-1, checkpoint inhibitors like nivolumab can restore T-cell activity against cancer cells.

"PD-1 puts a brake on immune response, and nivolumab releases the brake," explained Bruno Sangro of Clinica Universidad de Navarra in Pamplona, Spain, who presented findings from Checkmate 040 at last year's Liver Meeting. Study results were also recently published in The Lancet.

This phase 1/2 trial enrolled 262 people with compensated cirrhosis and advanced HCC whose tumours could not be surgically removed. Most were men and the average age was 63 years. Two-thirds had previously used sorafenib. About a quarter had HBV, another quarter had HCV and half had neither virus. Around 70% had metastases, or spread of cancer beyond the liver.

One part of the study included 154 people who experienced disease progression on sorafenib or were unable to tolerate it. Overall, 14% of this group showed some degree of response, or tumour shrinkage, according to a Bristol-Myers Squibb press release. Of these, 2% had complete responses and 12% had partial responses; about another 40% had stable disease. Among the 22 participants classified as responders, most were still responding at six months and 55% had responses lasting at least a year. Responses occurred regardless of PD-1 expression status or HBV or HCV infection.

Treatment with nivolumab was generally safe. More than 10% of treated participants had seriously elevated liver enzymes and 5% developed immune-mediated hepatitis requiring corticosteroids. The major concern with checkpoint inhibitors like nivolumab is immune-related adverse events; the drugs work by restoring immune responses against cancer cells, but they can also cause excessive inflammation of healthy tissue.

Nivolumab is the first immunotherapy approved for liver cancer. It is indicated for people with HCC who were previously treated with sorafenib. Data presented at this year's American Society of Clinical Oncology annual meeting showed that people who had never used sorafenib had somewhat better long-term outcomes on nivolumab, but the FDA has not yet approved nivolumab for this group. There are no restrictions based on PD-1 expression level. Nivolumab is administered by intravenous infusion every two weeks until disease progression or unacceptable toxicity.

Nivolumab is currently approved by the European Medicines Agency (EMA) for treatment of advanced melanoma, non-small cell lung cancer, kidney cancer and some types of lymphoma, but not yet for HCC. In the US it is also approved for thyroid cancer.

Continued approval of nivolumab for HCC may be contingent upon clinical benefit being demonstrated in later-stage trials, according to the press release. CheckMate 459, a randomised phase 3 study comparing nivolumab to sorafenib for first-line treatment of advanced HCC, is currently enrolling participants.

Bristol-Myers Squibb has decided to delay seeking a European Union licence for the use of Opdivo for HCC until it has data from further clinical trials. A licensing application was withdrawn in July 2017 after the scientific committee of the EMA concluded that the lack of data from studies comparing nivolumab to other therapies made it impossible to determine whether the benefits of treatment with the drug outweighed the risks.