Emerging Agents Offer New Hope in HCC


Amit G. Singal, MD, discusses the evolving armamentarium of treatment options for patients with hepatocellular carcinoma.

Amit G. Singal, MD

Amit G. Singal, MD

Amit G. Singal, MD

Hepatocellular carcinoma (HCC), a disease that accounts for approximately 90% of liver cancers worldwide, is often diagnosed in the advanced stage where treatment options have been limited, according to Amit G. Singal, MD. However, recent data have led to first- and second-line changes in the landscape.

For example, in August 2018, the FDA approved lenvatinib (Lenvima) as a first-line treatment for patients with unresectable hepatocellular carcinoma, based on data from the phase III REFLECT trial.

The trial showed that lenvatinib was noninferior to sorafenib (Nexavar) in the frontline setting, which was the established first-line standard of care. Median overall survival (OS) was 13.6 months on the lenvatinib arm compared with 12.3 months for those who received sorafenib.1 In terms of progression-free survival (PFS), lenvatinib and sorafenib were associated with a median PFS of 7.4 months and 3.7 months, respectively. Toxicity data were comparable in the 2 arms.

More recently, the REACH-2 trial highlighted ramucirumab (Cyramza) as a promising second-line therapy; high levels of alpha-fetoprotein (AFP) also emerged as a potential biomarker predictive of response to this treatment. This randomized, placebo-controlled, phase III study compared ramucirumab with placebo in patients with advanced HCC following first-line sorafenib.

Median OS was 8.5 months in the ramucirumab arm versus 7.3 for placebo. PFS was significantly improved for patients treated with ramucirumab at 2.8 versus 1.6 months, respectively. Moreover, ramucirumab reduced the risk of death by 29% for patients with high AFP (≥400 ng/mL).2

OncLive: What were the key points from your presentation?

In an interview with OncLive® at the 2018 State of the Science Summit™ on Gastrointestinal Cancers, Singal, associate professor and medical director of the Liver Tumor Program and clinical chief of Hepatology at UT Southwestern Medical Center, discussed the evolving armamentarium of treatment options for patients with HCC.Singal: HCC is a cancer that is actually increasing in incidence and mortality in the United States. While we are making great progress in other cancers, the relevance and unmet need of HCC is rapidly increasing. Over the last decade, the HCC incidence has more than doubled, according to some data we have. One of the things we talked about is some of the interesting and exciting progress made in terms of treatment, particularly in advanced HCC management. This is important because most HCC cases occur in the advanced stage when they aren't eligible for curative therapies.

The progress we have made with systemic therapies will benefit patients in terms of their survival. The first systemic therapy we had for HCC was approved about 1 decade ago. When that came out, people were excitedly saying, "This is the first step, but we anticipate many more therapies coming out over the next several years."

In the years that followed, all we had was negative trial after negative trial, and then more negative trials. Then, in the past year, we had an explosion of positive trials, both in the frontline and second-line settings. We had the REFLECT trial, which was a positive study comparing lenvatinib with sorafenib. It showed that lenvatinib has noninferior survival to sorafenib. Now we have first-line treatment options for patients with advanced HCC.

With these recent advancements and FDA approvals, how important is sequencing?

Furthermore, we finally have treatment options for second-line therapy. This means that if patients fail on lenvatinib or sorafenib, or if they progress, we have therapies we can use for those patients as well. We've had the RESORCE trial [with regorafenib] and the CheckMate-040 trial [with nivolumab]; both are positive and have FDA approval for these agents. Finally, I briefly touched on the CELESTIAL and REACH-2 studies [of cabozantinib (Cabometyx) and ramucirumab, respectively], which are positive trials in the second-line setting but are awaiting FDA approval.This is going to be the biggest question. With all these tools in your toolbox, how do you decide which agents to use and when to switch? We've made progress in terms of making these agents available. The next step is how to determine the best agent to use first, and when we should switch. When do you declare that this patient is no longer responding?

Please provide an analysis of the CELESTIAL and REACH-2 trials.

Right now, we use simple methods, such as imaging. We follow them on therapy every couple of months; we do an MRI on the abdomen. If we see the disease progressing, we switch to a second-line therapy. Similarly, if they're not tolerating it because of side effects, that would also be an appropriate time to switch. This is an area where we're going to have to make advancements over the next couple years.CELESTIAL was a trial that compared cabozantinib versus placebo in the second-line setting. Of interest, many of the patients—actually about 25% of the cohort—received 2 prior lines of systemic therapy, suggesting that cabozantinib could be effective as a third-line agent. In short, cabozantinib improved survival in the second-line setting versus placebo.

REACH-2 was the more interesting trial of the pair. It actually was informed by a negative phase III trial. Initially, ramucirumab was tested against placebo as a second-line therapy. After a posthoc analysis, it was discovered that there was potential benefit in patients who started with a high AFP level.

Is there anything on the horizon you are particularly excited about?

There were some intriguing data with atezolizumab (Tecentriq) and bevacizumab (Avastin). Can you highlight this?

With all of this information, what would be the piece of advice you would give to a community oncologist treating liver cancer?

This is what initiated REACH-2. It tested ramucirumab against placebo in patients with high AFP; they found a benefit in those patients. The great thing about this, once again, is now we have more therapies. REACH-2 was actually the first time [a trial suggested] a possible biomarker.We anticipate a lot of new agents and improved therapies over the next few years. We spoke about nivolumab being evaluated in a second-line setting in CheckMate-040. However, we also anticipate first-line results for nivolumab against sorafenib. This is from the CheckMate-459 trial. Those results should be coming out later [in 2018]. If this is a positive trial, this would revamp the entire landscape of how we approach HCC. The other trials that are coming out include a KEYNOTE trial, which is looking at another immunotherapy (pembrolizumab). This would once again add to our toolbox.Phase I results for this showed a promising signal in terms of response. About 60% of patients responded to this combination, although the numbers are quite small at this time. The FDA granted breakthrough therapy designation to this, so it is essentially being fast-tracked. Now the phase III trial has started, and we anticipate results. It's interesting because we've mainly been using single-agent therapy.It's an exciting time because we finally have lots of therapies we can choose. The big thing to remember is these advanced HCC systemic therapies are still happening in a larger landscape. We have to remember that we still have curative therapies available. There are good data that show multidisciplinary treatment improves outcomes in patients with advanced disease. It's important that we use these emerging agents in the right patients. We need to start our patients on the appropriate therapy, follow them for adverse events and response, and then sequence, so we can get the best possible outcome.


  1. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial [published online February 9, 2018]. Lancet. doi:10.1016/S0140-6736(18)30207-1.
  2. Zhu A, Kang YK, Yen CJ, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol. 2018;36(suppl; abstr 4003).
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