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FDA Approves Nivolumab Immunotherapy for Liver Cancer


In September, the U.S. Food and Drug Administrationgranted accelerated approval for nivolumab (Opdivo), an immunotherapy drug that restores T-cell anti-tumor activity, for people with hepatocellular carcinoma (HCC).

Nivolumab, an antibody that blocks the PD-1 receptor, was approved for patients 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, 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.

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(programmed death protein 1), a cell-signaling 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 findingsfrom 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 tumors 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 patients who experienced disease progression on sorafenib or were unable to tolerate it. Overall, 14% of this group showed some degree of response, or tumor 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 after 6 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 patients 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 2 weeks until disease progression or unacceptable toxicity.

Nivolumab is currently approved by the EMAfor treatment of advanced melanoma, non-small cell lung cancer, kidney cancer, and some types of lymphoma, but not yet for HCC. In the U.S. 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 randomized Phase 3 study comparing nivolumab versus sorafenib for first-line treatment of advanced HCC, is currently enrolling participants.



Food and Drug Administration. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. Press release. September 22, 2013.

Bristol-Myers Squibb. Bristol-Myers Squibb’s Opdivo (nivolumab) Receives FDA Approval for the Treatment of Hepatocellular Carcinoma Patients Previously Treated with Sorafenib. Press release. September 22, 2013.