Regorafenib Renews Hope in Hepatocellular Carcinoma

Jordi Bruix, MD

After numerous failed attempts to uncover an effective second-line systemic therapy for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib, optimism was fading in the industry; however, that all changed with regorafenib (Stivarga), a novel second-line agent that is currently being considered for approval by the FDA, said Jordi Bruix, MD, at the 2016 AASLD Liver Meeting.

“Before regorafenib, the field was a bit pessimistic. Everything had failed,” said Bruix, head of the Barcelona Clinic Liver Cancer (BCLC) at University of Barcelona. “Now something is positive, and positive leads to possibilities. The field is back.”

HR 0.63; 95% CI 0.50-0.79; p<0.001

Regorafenib demonstrated efficacy as a second-line therapy for HCC in the phase III RESORCE trial, in which the median overall survival (OS) was 10.6 months with regorafenib plus best supportive care compared with 7.8 months for placebo plus best supportive care. This represented a 37% reduction in the risk of death ().

In an interview with OncLive, Bruix, who was the lead investigator of the RESORCE trial, discussed the impact of regorafenib and future advances on the horizon for the agent in HCC.

OncLive: How has the role of systemic therapy for HCC evolved in recent years?

Bruix: Systemic therapy for HCC was an unmet need for several years. Ten years ago I was the principal investigator for a trial that proved the benefits of sorafenib in patients with HCC. This was a landmark and at that time everybody thought that we would have a series of success with combinations, new agents, and so on. What has happened is exactly the opposite. Every time first-line combinations with sorafenib have been tested, they’ve failed. In second-line, in patients that have progressed with sorafenib, all the trials that were in place with different agents also failed. It became very pessimistic.

Then regorafenib appeared, which has a similar profile to sorafenib, but with some variations in the potency and the tolerance. There was a trial, with patients which have progressed on, but tolerated sorafenib. What we have shown is that regorafenib very much clinically impacted survival. It delayed tumor progression and progression-free survival was also significantly improved. We have again, success as we had with sorafenib, and this will become now a sequential therapy, starting patients on sorafenib and then when they progress moving them to regorafenib.

Now, what we have to do is begin to work in third-line, because survival is dismal, and these patients deserve even more research to get other agents that will surpass sorafenib and regorafenib.

How big of an impact will regorafenib have in HCC?

The clinical improvement is very relevant. It is clinically meaningful to have an improvement in survival that is more than 30%. It makes a big jump in terms of life expectations.

The other thing that is important is that it is well tolerated. Regorafenib had a bad reputation in colorectal patients because there it was said to be poorly tolerated because the patients had undergone several other treatments before receiving regorafenib. In GIST, which is another indication of regorafenib, the tolerability is quite good, and in HCC we only had 10% of the patients that had to interrupt treatment because of adverse events. This means that 90% of the patients tolerated the drug properly, with some dose adjustments.

We also looked at patient reported outcomes and quality of life, and there is no clinical impairment that is clinically significant due to regorafenib. So we have something that is effective, and safe. Perfect.

What do you see on the horizon for regorafenib in HCC?

Everyone is talking about the immune modulators and the possibility of combining those with other agents and that could be considered with regorafenib.

There is also talk about moving regorafenib into the first-line as well, but this is not proven to be safe yet and has to be carefully explored.

But both of these right now are wishful thinking. What we have right now, is real life, and that is that in practice this is an effective second-line treatment, and that is good news.

What is it about the mechanism of action of regorafenib that causes it to be more effective than some of the past agents that have been investigated in HCC?

Sorafenib and regorafenib are both not only very anti-angiogenic and anti-proliferative, but they target the stromal cells. There are more and more signals that sorafenib, and probably regorafenib, change the stromal population, and this induces a kind of change in the biology that results in the tumor freezing and not progressing for long. I think this is what makes it different than the agents that have failed. This is not well known because when we say, targeted therapies, what happens with sorafenib and regorafenib is that they have several targets. It is a target that is not selective and we don’t really know the targets that are beneficial and that ones that are not.

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Median progression-free survival was 3.1 months in the regorafenib arm compared with 1.5 months in the placebo group, representing a 54% reduction in the risk of progression or death (HR, 0.46; 95% CI, 0.37-0.56; P <.001). The median time to progression in the regorafenib group was 3.2 versus 1.5 months with placebo (HR, 0.44; 95% CI, 0.036-0.55; P <.001).