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US FDA approves pembrolizumab immunotherapy for liver cancer

Liz Highleyman
12 November 2018

The US Food and Drug Administration last week granted accelerated approval for pembrolizumab (Keytruda), an immunotherapy drug known as a checkpoint inhibitor, for people with hepatocellular carcinoma (HCC).

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 HCC, the most common cancer that originates in the liver. 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.

Liver cancer is often diagnosed late and is difficult to treat, making it a leading cause of cancer death worldwide. Traditional chemotherapy is not very effective against this type of cancer. Standard first-line therapy includes the kinase inhibitor targeted therapies sorafenib (Nexavar) and lenvatinib (Lenvima), with regorafenib (Stivarga) as a second-line option.


hepatocellular carcinoma (HCC)

Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.

Pembrolizumab is an antibody that blocks the PD-1 receptor, an immune checkpoint on T cells. PD-1 plays a role in regulating immune responses by suppressing excessive immune activation. Some tumours can hijack PD-1 to disable immune responses against them. By blocking the interaction between PD-1 and its binding partner, known as PD-L1, checkpoint inhibitors can release the brakes and restore T-cell activity. Pembrolizumab is currently approved by the EMA for several types of advanced cancer.

Approval of pembrolizumab for HCC was supported by findings from the phase 2 KEYNOTE-224 trial. While response rates were not particularly high for HCC compared with some other types of cancer, existing treatment options are not very effective and the checkpoint inhibitor performed better than standard therapy.

As described in the 3 June 2018 edition of The Lancet Oncology, KEYNOTE-224 included 104 people with advanced liver cancer who either experienced disease progression on sorafenib or were unable to tolerate it. Most were men and the median age was 68 years. About 20% had HBV, a quarter had HCV and 9% had both viruses. Two-thirds had cancer that had spread beyond the liver.

All study participants were treated with pembrolizumab for about two years or until disease progression or unacceptable side-effects occurred; there was no placebo or comparative intervention arm.

The overall response rate, or the proportion who saw their tumours shrink, was 17%, including one complete response. Another 44% had stable disease without progression. Among the 18 responders, 12 were still responding after 9 months on therapy. The median progression-free survival was 4.9 months and the median overall survival was 12.9 months. Responses were similar regardless of PD-1 levels or HBV or HCV status.

Treatment with pembrolizumab was generally safe, but side-effects were common. About a quarter experienced severe treatment-related adverse events (most often elevated liver enzymes) and 5% discontinued therapy for this reason.

A major concern with checkpoint inhibitors is immune-related adverse events. The drugs work by restoring immune responses against cancer, but they can also cause inflammation of healthy tissue. Four people in this study experienced severe immune-mediated adverse events and there was one treatment-related death. Three people developed immune-mediated liver inflammation, but none saw increases in HBV or HCV levels.

Two ongoing pivotal phase 3 studies, KEYNOTE-240 and KEYNOTE-394, are evaluating pembrolizumab monotherapy for second-line treatment of HCC and other studies are looking at pembrolizumab plus targeted therapies, according to Merck.