Regorafenib Success Revives Hope in HCC

Angelica Welch
Published: Saturday, Apr 22, 2017

Jordi Bruix, MD

Jordi Bruix, MD

Findings from the phase III RESORCE study showed that regorafenib (Stivarga) is an effective second-line treatment for patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib (Nexavar). Based on the findings, the FDA granted regorafenib a priority review in this setting.

Since the approval of sorafenib in 2007, regorafenib is the only systemic treatment shown to provide survival benefit in HCC. After a decade of failed attempts at developing a successful second-line therapy for patients with advanced HCC, the RESORCE findings have excited a field that had become sullen, said Jordi Bruix, MD, head of the Barcelona Clinic Liver Cancer at University of Barcelona.

“The field is optimistic again and now, everybody thinks that improvements further from sorafenib can take place,” said Bruix.

During the 2017 International Liver Congress (ILC), Bruix presented the findings of a comparison of modified (m)RECIST and RECIST 1.1 assessments in the RESORCE trial, for which he is the lead author. Bruix and his fellow investigators assessed tumor response and progression by the HCC-specific mRECIST and RECIST 1.1 in a prospective comparison.

In an interview with OncLive at the ILC, Bruix, discussed the success of regorafenib in HCC and its impact on the field going forward.

OncLive: How has the oncology community reacted to the success of regorafenib in the second line?

Bruix: The RESORCE trial has been a big success. The past 10 years, after the approval of sorafenib, have been a series of failures. Every drug that have been tested alone or in combination, has failed both in first line and second line. The regorafenib trial versus placebo in patients that have progression on sorafenib showed a really significant improvement in survival. Not to say our findings were surprising, but it took everyone out of this sullen feeling—that everything would fail and all the trials would be negative, the field was depressed.

This follows what has happened in other cancers such as colorectal and breast, where everything was negative at the beginning. And hopefully, we will have third-line therapies and combinations and first and second line. So, this is something that I believe will have an impact, not only for the patients, but also for the field to have a more optimistic view of the future.

In light of the RESORCE results, how do you anticipate regorafenib is going to be put into practice?

Regorafenib was already approved for patients with colorectal cancer and gastrointestinal stromal tumors. It is sad that in colorectal cancer the drug is poorly tolerated, as it has raised some reluctance in the oncology community that deals frequently with metastatic colorectal cancer. This has raised doubts about the real clinical benefit of regorafenib. The population with metastatic colorectal cancer is different from cirrhotic. The population from the SHARP study had received a lot of first- and second-line intervention, and finally in the third line where they are exposed to TKIs, which makes a big difference.

The patients in RESORCE had already tolerated sorafenib, and this is instrumental—this population has already been exposed to the family of sorafenib and regorafenib. The physicians that manage sorafenib are experts in managing the side effects, and as a result, this was a combination of a drug that is effective, patients that were exposed, and physicians that are experts, which was instrumental to having a positive result. 

I think the idea that regorafenib is toxic and poorly tolerated has to be defined according to different populations and indeed, in RESORCE, we had quality of life measurements. None of the different parameters were impaired in a clinically significant manner, according to standard. What we have is a drug that is effective, properly tolerated—the doses have to be adjusted, but in general it’s a good balance of efficacy and safety and tolerance.

Could you provide an overview of the comparison study of (m)RECIST and RECIST 1.1?

One of the concepts that has been debated for several years in cancer, and specifically in HCC, is the best system to assess response and progression. In HCC, we have a lot of locoregional treatments—ablation, transcatheter arterial chemoembolization (TACE), and so on—that induce necrosis. So, it was already in place for us to assess the efficacy of ablation or TACE by measuring necrosis, and these were the criteria that we developed back in 2001. 

When we developed the trial for sorafenib–SHARP–we refined the criteria to define progression in patients with HCC. In the liver, you may have new nodules that are microgenetic nodules and are not really progressive in terms of cancer. We redefined the definition for these types of nodules, and we also discarded plural effusion as progression if not proven by cytology that they were malignant, that way, we had to refine RECIST. 

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