Rapid Progress in HCC Leads to Sequencing Challenges

Andreas Kaubisch, MD

A slew of regulatory approvals for novel agents, such as TKIs and checkpoint inhibitors, has significantly advanced liver cancer treatment in recent years, according to Andreas Kaubisch, MD; however, with this rapid progress comes the challenge of learning how to best sequence these drugs in practice.

“There have been several new drug approvals for the treatment of patients with liver cancer. It's a very exciting time in oncology, not just liver cancer itself,” said Kaubisch. “We look forward to new, innovative trials examining different drugs and ways to manipulate immunotherapy. Hopefully, all of this will help us achieve somewhat better outcomes for our patients.”

Before the emergence of sorafenib (Nexavar), there were limited systemic therapeutic options available for patients with hepatocellular carcinoma (HCC). Since the agent’s approval, lenvatinib (Lenvima), regorafenib (Stivarga), cabozantinib (Cabometyx), nivolumab (Opdivo), pembrolizumab (Keytruda), and ramucirumab (Cyramza) have been added to the treatment arsenal for use across several settings.

With the emergence of these novel approaches come sequencing challenges, according to Kaubisch, especially regarding immunotherapeutic agents.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Kaubisch, an associate attending physician at Montefiore Medical Center and Albert Einstein College of Medicine, shed light on systemic therapies available in liver cancer and some of the practice-changing phase III trials that have read out in the space.

OncLive^®: What are some key updates in the treatment of liver cancer?

Kaubisch: There are recent practice-changing phase III studies in liver cancer—all the way from the SHARP trial with sorafenib, which led to its approval about a little more than a decade ago, to the most recent phase III studies that have established drugs such as lenvatinib as a second option for first-line treatment. I also discussed several second-line trials, such as the RESORCE and REACH trials, which looked at ramucirumab, regorafenib, cabozantinib, nivolumab, and pembrolizumab; all of these agents were approved fairly recently as second-line treatment for patients with liver cancer.

Could you expand on these available options?

We have basically had two or three different classes of drugs that have come onto the scene in terms of management options for those with liver cancer. Sorafenib is the original drug in this group for liver cancers, the TKIs; it is also an oral drug. The other drugs in that class that have also found use in liver cancer are regorafenib, which is very similar to sorafenib, as well as cabozantinib, which is another oral TKI. Immunotherapy drugs have made it onto the market in HCC as well; that has been very exciting for us. Nivolumab first, pembrolizumab second, and lastly, ramucirumab, which is an antibody to VEGF and also is the most recent approval in the second-line treatment of patients with liver cancer.

Could you discuss the pivotal REACH trials with ramucirumab and the key findings from that research?

In the original REACH trial, there was a signal with ramucirumab; it wasn't quite as impressive as the study designers had hoped. However, one of the subgroup analyses [of that trial] showed that patients with liver cancer who have an alpha-fetoprotein (AFP) [value] of 400 ng/mL or higher seemed to do better on that drug compared with placebo. The second trial, [REACH-2], was designed and almost 300 patients were enrolled and randomized to receive ramucirumab versus placebo. Those enrolled were “good” patients with HCC and AFP [values] above 400 ng/mL; there was a modest but statistically significant benefit in survival in [those who received ramucirumab] in that study. Subsequently, the drug got approved for use in the second-line setting.

Are there any unanswered questions with ramucirumab?

It's a very recent approval and I believe we all have to get used to applying its use to our practice and getting our own experience [with the agent]. The approval is for patients with HCC who have an AFP of ≥400 ng/mL and have been previously treated with sorafenib. Like all drugs, we experiment a little bit in terms of when to apply it and how to use it. We all have to get a little bit familiar with [all of] the drugs and see [what experiences we have with] them in clinical practice. It’s not quite established how and when these drugs are going to get used, but we know when we're supposed to be using them [based on their indications].

You also mentioned cabozantinib. What data have been reported with that agent in the second-line setting?

Cabozantinib is another TKI that was tested against placebo for patients who had been previously treated with sorafenib. Again, like many of these second-line studies, we saw a modest improvement in survival, and its toxicity profile is a little similar but not exactly the same, to that of the other TKIs. I believe cabozantinib is a valid second- or third-line option for the management of patients with advanced liver cancer.

What is the optimal use of immunotherapy in this field?

The [optimal] use of many of these drugs is not completely established yet. We have questions about sequence in terms of what drugs to use first versus what to use second. We're getting additional data in terms of combinations. [Based on] early trials, it looks like [this approach] might be more active [than monotherapy], but we're waiting for larger trials to make that part of our practice. [It’s important to remember that] the studies that have led to the approval of immunotherapy drugs are fairly small, each in the order of having enrolled 100 to 150 patients. [These agents generally have shown a] good safety signal, a well-known toxicity profile, and some nice signs of activity. Again, [we have seen] modest response rates, but some patients do exceptionally well, so that has been encouraging for us.