Michael Morse, MD, FACP, MHS
The field of hepatocellular carcinoma (HCC) has come a long way in a short time, said Michael A. Morse, MD, FACP, MHS, with several agents entering the treatment landscape and research expanding beyond the use of a single-agent checkpoint blockade to improve survival.
“We may now be in an era where we may soon see data from patients who are less advanced, [for whom we are] using a checkpoint blockade or a checkpoint blockade in combination with a local regional therapy or with surgery,” said Morse. “Even the idea of what constitutes first-line [treatment is changing], where many patients used to receive local regional therapies. Now may be an area where checkpoint blockade has an important role.”
Up until a few years ago, sorafenib (Nexavar) had been the only FDA-approved agent available for the first-line treatment of patients with advanced disease. After several negative trials with other drugs, lenvatinib (Lenvima) entered the first-line landscape, and was shown to be noninferior to sorafenib in the phase III REFLECT trial. With the August 2018 FDA approval, patients with HCC finally had another first-line treatment option available to them.
Second line is also an area for which there were previously no standard options and now there are 2 FDA-approved tyrosine kinases (regorafenib [Stivarga] and just recently approved, cabozantinib [Cometriq] and 2 anti¬–PD-1 therapies (nivolumab[Opdivo] and pembrolizumab [Keytruda]).
Also eagerly awaited in the second-line setting is the FDA review of ramucirumab (Cyramza), which, according to Morse, differs from the other drugs on the market in that it is a recombinant monoclonal antibody that binds to VEGFR2 and for which there may be a biomarker. In the phase III REACH-2 trial, the agent demonstrated improved overall survival (OS) compared with placebo in patients with alpha-fetoprotein (AFP) levels of at least 400 ng/mL who received previous treatment with sorafenib.
In an interview during the 2019 OncLive®
State of the Science Summit™ on Gastrointestinal Cancers, Morse, a medical oncologist at Duke Cancer Institute, highlighted the latest ongoing research in HCC and predicted what future treatment might look like in this field.
OncLive: What have been some recent advances in the treatment of patients with HCC?
: HCC has really undergone an enormous change very recently. For a long time, for advanced disease, we basically only had sorafenib, and every drug that came along failed against it. For first line therapy, the important advance is that lenvatinib showed noninferiority for overall survival compared with sorafenib in the REFLECT trial. There were several other endpoints that had interesting results. There was a better PFS with lenvatinib and a better response rate. The agents have slightly different toxicities. Both of them are appropriate for first-line treatment and so, I discuss them both with patients. Now, there is at least another drug available to patients, which, at least in secondary endpoints, has some advantages over sorafenib.
Could you discuss the recent data with ramucirumab? What is the hope for this agent?
In the second-line setting, we now have 2 FDA-approved TKIs—regorafenib (Stivarga) and cabozantinib (Cabometyx)—and we have 2 FDA-approved immunotherapies—pembrolizumab (Keytruda) and nivolumab (Opdivo). You would think there wouldn't be room for any more drugs, but of course, there are several drugs still being studied. The furthest along and that met its endpoint is ramucirumab. Where ramucirumab may have some differences [from the others] is, it's not a TKI and it's not an immunotherapy; it binds to VEGFR2. Also, its side effect profile is very different than the other therapies. It was originally studied in the REACH trial, and in that study, it didn't meet its endpoint compared with placebo in all comers who had been previously treated with sorafenib. Because it didn't meet its endpoint, [investigators] were naturally trying to find out, why wouldn't it work? We have all these other therapies now that are working, what's so different there?
They found out that patients with high AFP levels, specifically higher than 400 ng/mL, did seem to benefit from the drug, and there's even a potential biologic explanation for that in that the group of tumors who have high baseline AFPs also seem to have transcription profiles suggesting growth factor signaling and VEGF/VEGFR2 pathway that might affect sensitivity to ramucirumab. It may be the case that high AFP identifies a special subgroup of HCC.