R. Kate Kelley, MD, discusses the incidence of and risk factors for HCC, and emphasizes the sequence of clinical trials that characterized the field in 2017.
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.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.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.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.
The efficacy data prompted a larger expansion cohort, and that was born out of the response rates. The patients who had received prior sorafenib, and potentially more than 1 prior therapy, had a median overall survival (OS) greater than 15 months. This is a provocative signal in HCC. This trial has now expanded to include a nivolumab plus ipilimumab (Yervoy) cohort. A nivolumab plus cabozantinib combination is expected, as well. It’s growing into a study with more than 600 patients. That’s one study to watch in which we will expect many more results ahead.
In addition, there are data from KEYNOTE-224 in which pembrolizumab was examined in a strict second-line population after sorafenib. The results were presented by Dr Andrew Zhu at the 2018 Gastrointestinal Cancers Symposium. That study reinforced the data from the CheckMate-040 trial. Results from KEYNOTE-224 showed an acceptable safety profile with pembrolizumab that is comparable to nivolumab. There were no increased hepatic adverse events compared with what we would expect in another population. Although the survival data aren’t mature yet, the length of response duration is promising. Now, we have another selection of data suggesting there’s a real benefit signal from PD-1 inhibitors.
There are now large studies looking at the combination of PD-L1 and CTLA-4 inhibitors, specifically durvalumab and tremelimumab. We presented the phase I results at the 2017 ASCO Annual Meeting. The results showed a preliminary unconfirmed response rate of about 25% and very reassuring safety in line with what we’d expect with either drug alone. The combination showed no significant increase risk in safety in a small 40-patient phase I setting. That has also led to an expanded and accruing randomized phase II trial with an expected enrollment of 400 patients.
That has prompted a recently activated phase III trial called HIMALAYA comparing 4 different treatment arms with the standard of care, sorafenib. The treatment arms are investigating 2 different combinations of durvalumab and tremelimumab to durvalumab alone. The study is on target to be the largest randomized trial in the history of HCC. This is just a snapshot of the studies underway; there are many to come.For the first time in the history of the disease, we will have multiple therapies for advanced HCC. Although it will be challenging, HCC is an extremely interesting area for research. It’s also an extremely promising area for patients because we are starting to realize that there may be immunologic differences between fatty liver and hepatitis B- and C-related liver disease. This may depend on whether the viral disease has been treated or not and the microenvironment may play a huge role as well. Although it may be confusing to integrate these therapies at first, we will be able to personalize medicine and individualize treatment for these patients.
Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. In: Proceedings from the 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, California. Abstract 209.