Moving the Needle in HCC: International Experts Weigh In - Episode 12

Second-Line Systemic Therapy in HCC


Richard S. Finn, MD: For 10 years, we’ve had sorafenib as the only approved agent in liver cancer. There have been great efforts to improve on something better in the frontline setting. But probably the largest unmet medical need, historically, has been, what do we do when patients really are progressing on sorafenib?

Jordi, you were one of the leads in the RESORCE study, which was the basis for the registration and approval of the first drug in the second-line setting, regorafenib. Regorafenib, like sorafenib, is a multitargeted kinase inhibitor. It has a little broader activity in certain pathways. You had done a single-arm, relatively small phase II study that showed some activity. Can you tell us about the patients who went into the RESORCE study and how that data might impact our management of patients in the frontline setting, let alone the second-line setting?

Jordi Bruix, MD: Sorafenib was already explained. Regorafenib looks, from the outside, similar in mechanism, but it has some specific differences that make it a bit more powerful. When targeting other targets, we felt a phase II study was needed to confirm that it was safe. We did an initial study that collected, as you said, a limited number of patients, to prove that in patients who had tolerated sorafenib, regorafenib—even if it was potentially more powerful—would be safe. This was the case. The signal was that it may have a special sensitivity to detect signals, and the vision was to move forward into a phase III study.

We decided to do it in patients that were tolerant to sorafenib to avoid the risks that could have happened in naive patients, as was the case for sunitinib. That was also more powerful, but they didn’t use liver failures and prime death. So, we said “Perfect.”

Tolerance was defined, in an arbitrary manner for the last 28 days, to receive 20 days of the half-dose of sorafenib. This helped to sort out those who would not tolerate the drug—those who are, let’s say, less committed to adhere to treatment. It sorted out the good physicians who were able to adjust. One of the important persons in oncology teams—and this has not been mentioned—are nurses. Nurses are key to educate, filter the consults, and make sure that everybody is in line. And this is often missing in multidisciplinary teams.

Having said that, in the time between the last pill of sorafenib and the first pill of regorafenib, I think it has to be maintained for at least 2 weeks. We had a trial that was quite clean in a well-defined population comparing treatment versus placebo, and we had a 30% increase in the life expectancy. Safety was there. We did not have major challenges compared to what we saw in colorectal cancer.

Richard S. Finn, MD: You said safety is there, and I think the approval of regorafenib in liver cancer is relatively new. Regorafenib has been used in the colorectal space and the gastrointestinal stromal tumor space. Can you comment, specifically, on the safety in a liver cancer population?

Jordi Bruix, MD: The side effects of regorafenib are arterial hypertension, the hand-foot-skin reaction, a bit of diarrhea, and a bit of ischemia. But they can be managed with dose adjustments. It is the concept, in oncology, that this is toxic because in colorectal cancer patients, it was felt as toxic. Colorectal cancer patients are patients that have suffered several lines of treatment, intervention, and so on, so they are a bit more ill and burned out.

In liver cancer, only 10% of the patients had to stop treatment and interrupt it because of adverse events related to the drug. What does it mean? It means that it was well tolerated and it can be dose adjusted, and the same happens in GIST. It’s not that it’s a mistake in liver cancer, it’s probably that we have to pay attention to the population.

Richard S. Finn, MD: That’s great. Dr. Marshall, I’m going to close this segment with your comments. We presented, at the Gastrointestinal Cancers Symposium meeting a few months ago, that for patients who were on the RESORCE study, from the time they started sorafenib—and this is obviously a subset of patients who were on the study—to the time of death, their survival was 26 months. That’s a long time for patients with advanced liver cancer. Now that we have a continuum of treatment for liver cancer, does that change when you refer patients for systemic treatment as an interventional radiologist?

Richard H. Marshall, MD: I think it does. It makes me aware that there is something else that can be done and that I should act quickly to get those patients back to their oncologist and start those treatments. I think, absolutely, it needs to be better defined as to when I should stop, and when systemic therapy should start.

Richard S. Finn, MD: I think it’s an important point, not only to think about their tumor, but also their liver function, because if a patient gets declining liver function from extra procedures, then that can compromise their ability to get proven active agents.

Transcript Edited for Clarity