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HCC Trials Spur Treatment Landscape Forward

Caroline Seymour
Published: Wednesday, Apr 11, 2018

R. Kate Kelley, MD
R. Kate Kelley, MD
Clinical trials continue to investigate the use of immunotherapy agents in advanced hepatocellular carcinoma (HCC), especially with the phase III CheckMate-459 trial in which nivolumab (Opdivo) is being compared with sorafenib (Nexavar) in the frontline setting.

“CheckMate-459 has completed accrual and will likely be the next big story in HCC because it has the potential to change not only the standard of care, but the entire treatment landscape,” says R. Kate Kelley, MD.

Findings from additional immunotherapy trials are expected to have an impact on the landscape. Results from the phase II KEYNOTE-224 trial, a single-arm study looking at the use of the PD-1 inhibitor pembrolizumab (Keytruda), showed a 16.3% overall response rate (95% CI, 9.8%-24.9%), with 1 complete response, in patients with advanced-stage disease who progressed on sorafenib.

Moreover, the randomized, multicenter, phase III HIMALAYA trial will have 4 arms for patients with previously untreated, unresectable HCC with 2 regimens of durvalumab (Im nzi) plus tremelimumab, durvalumab monotherapy, and sorafenib alone (NCT03298451).

In an interview during the 2018 OncLive® State of the Science SummitTM on Gastrointestinal Cancers, Kelley, associate professor of clinical medicine, Department of Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the incidence of and risk factors for HCC, and emphasized the sequence of clinical trials that characterized the field in 2017.

OncLive®: What is the current state of HCC?

Kelley: HCC is dramatically on the rise; it’s the number 1 rising cause of cancer death in the United States. HCC is projected to increase even further because of rising risk factors like fatty liver disease, which is an epidemic in the Western world. Historically, we have only really had 1 systemic therapy for advanced disease, which is the multikinase inhibitor sorafenib. Sorafenib was approved in 2007 based upon the randomized phase III SHARP trial.

After the SHARP trial there was a string of negative trials, but newer studies are changing the landscape. Last year, 4 other HCC agents were reported in positive trials. In 2017, 2 drugs were approved in addition to sorafenib. Regorafenib (Stivarga) was approved as a second-line agent, and nivolumab was approved after first-line sorafenib.

In early 2018, we saw positive results from the REFLECT and CELESTIAL trials. REFLECT examined the use of frontline lenvatinib (Lenvima) and showed noninferiority to sorafenib. At the 2018 Gastrointestinal Cancers Symposium, CELESTIAL reported a benefit in the use of second- or third-line cabozantinib (Cabometyx) following sorafenib. All of a sudden, we have a very complex landscape. Now, the wildcard is nivolumab. I focused on nivolumab and the string of immunotherapy trials that have the potential to change the landscape even further.

Can you expand on the risk factors for HCC?

Obesity and being overweight are growing problems in the world. Having obesity and risk factors for metabolic syndrome such as diabetes, hyperlipidemia, and dyslipidemia can also lead to a condition called nonalcoholic fatty liver disease. This is a spectrum of disease ranging from mild changes to steatohepatitis, in which fat deposits in the liver lead to in inflammation. Similar to alcoholic hepatitis, hepatitis B, and hepatitis C, steatohepatitis can lead to fibrosis, cirrhosis, and mutations that result in cancer. Fatty liver and associated conditions with nonalcoholic fatty liver disease are now the number 1 cause of liver cancer in the United States.

What is the timeline of immunotherapy trials in liver cancer?

CheckMate-040 started as a simple phase I trial investigating dose escalation of nivolumab. This led to a series of dose expansions that showed striking and durable response rates of 15% to 20%, depending on whether it was investigator-assessed, or centrally reviewed. These rates were reflected across all nonviral, uninfected patient subgroups; this included patients without hepatitis B or C, and those with either hepatitis B or C.

The response rate was the first signal that something unusual was going on. The safety profile was also reassuring. Originally, we were worried that the HCC population with underlying hepatitis and liver disease might be susceptible to increased risk of hepatitis, hepatic decompensation, or viral reactivation. All of those things were carefully scrutinized in the phase I trial and no increased risk of liver events, hepatic decompensation, or viral flares was shown.

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