Novel Agents Offer Hope in Hepatocellular Carcinoma

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.

OncLive: What have been some recent advances in the treatment of patients with HCC?

Could you discuss the recent data with ramucirumab? What is the hope for this agent?

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.Morse: 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.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.

What are your thoughts regarding the KEYNOTE-240 trial with pembrolizumab?

Investigators went back and decided, “Let's do the REACH-2 trial in patients with AFPs greater than 400 ng/mL.” For the trial, patients were randomized to receive ramucirumab or best supportive care/placebo. In that setting, ramucirumab did meet its endpoint, showing a better OS and PFS. What’s going to be interesting is, if it gets FDA approval, will this be specifically for those high-AFP patients? Will it carve out that particular niche? Will it be for people who previously had a TKI and just aren't going to be able to tolerate a TKI, or maybe they would have contraindications to immunotherapy, or for whatever reason are not felt to be good immunotherapy candidates? Perhaps they have even been previously treated with these drugs, but it will offer another opportunity for patients who still have good performance status to move onto another therapy.The KEYNOTE-240 trial really was an attempt to show, in a randomized fashion, that pembrolizumab gave a better OS and progression-free survival (PFS) in patients who received prior systemic treatment. The importance of the study is that, to date, we only had data from single-arm trials of immunotherapy.

With nivolumab, we had CheckMate-040, and there, that agent showed a response rate that, depending on the subgroup, was anywhere between 15% to 20%. These were durable responses, enough so to get the drug approved [by the FDA for use] in patients who had been previously treated with sorafenib.

Similarly, KEYNOTE-224, a single-arm trial of pembrolizumab showed very similar response rate data. Therefore, when we're treating patients with these very preliminary data, we want to know: does it really show benefit compared with other therapies or best supportive care? The KEYNOTE-240 trial was an attempt to answer that.

Are there any specific trials that you’re excited to see the results of?

First of all, [results have] only been posted on the company website as a news release. We don't have data published in a peer-reviewed fashion, but it was announced that the trial "did not meet its endpoint." However, if you look at the data, it's clearly directionally positive for overall survival and progression free survival, but it did not meet statistical significance per the pre-specified statistical plan. To me, these data, in combination with previous data, show that pembrolizumab clearly still has activity, and it's still one of the options for second-line therapy.What everyone is waiting for, of course, is the CheckMate-459 trial, which is a randomized clinical trial evaluating patients receiving nivolumab versus sorafenib in the first-line setting. We had hoped for this data by now, but I suspect that the fact that it's taking a while reflects that patients with HCC are in general doing better. If that is a positive study for nivolumab, that opens the floodgates for all of the other studies that are ongoing now, which are mostly combinations. [This includes] dual checkpoint inhibitors in the HIMALAYA trial, or exploring a checkpoint blockade plus a targeted approach in a study of atezolizumab (Tecentriq) plus bevacizumab (Avastin).

What is your take-home message to your colleagues?

Coming along are about 6 or 7 studies of essentially TKIs plus checkpoint blockade. Therefore, I expect in the not-too-distant future, that it's not going to be just single-agent checkpoint blockade, but it's going to be checkpoint blockade plus some other drugs. Hopefully, that will really improve survival for patients.It’s not just where we've been, it's where we're going, and the data are coming fast and furious in all cancers—whether it's with targeted therapies, immunotherapies, or molecular analysis of tumors. The diseases that I take care of, historically, have been ones where there has been a lot of nihilism. With HCC, [the mentality was], unless you can do local regional therapy, why bother? Even with sorafenib, there are many patients who aren't treated because the feeling is that you may have toxicities—how much is it going to benefit the person? I've always been a believer, of course, that it does benefit people, and patients should at least know that these are therapeutic options.

Now, we have 2 frontline therapies, and we have studies that will soon report out with immunotherapy in the first-line setting. We have [6] FDA-approved drugs, and hopefully, we'll have a [seventh] shortly in the second-line setting [with ramucirumab]. Some drugs, such as cabozantinib, have been tested in second- and third-line setting, so we have third-line options for patients.

The point is: don’t be nihilistic about it anymore. There is a lot we can do for patients with HCC and it's not that it's an either/or in the future with our surgeries and our local regional therapies; we may be combining these drugs with these procedures.

Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9.